This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About Childhood Cancer Genomics

Research teams from around the world have made remarkable progress in the past decade in elucidating the genomic landscape of most types of childhood cancer. A decade ago it was possible to hope that targetable oncogenes, such as activated tyrosine kinases, might be identified in a high percentage of childhood cancers. However, it is now clear that the genomic landscape of childhood cancer is highly varied, and in many cases is quite distinctive from that of the common adult cancers.

There are examples of genomic lesions that have provided immediate therapeutic direction, including the following:

  • NPM-ALK fusion genes associated with anaplastic large cell lymphoma cases.
  • ALK point mutations associated with a subset of neuroblastoma cases.
  • BRAF and other kinase genomic alterations associated with subsets of pediatric glioma cases.
  • Hedgehog pathway mutations associated with a subset of medulloblastoma cases.
  • ABL family genes activated by translocation in a subset of acute lymphoblastic leukemia (ALL) cases.

For some cancers, the genomic findings have been highly illuminating in the identification of genomically defined subsets of patients within histologies that have distinctive biological features and distinctive clinical characteristics (particularly in terms of prognosis). In some instances, identification of these subtypes has resulted in early clinical translation as exemplified by the WNT subgroup of medulloblastoma. Because of its excellent outcome, the WNT subgroup will be studied separately in future medulloblastoma clinical trials so that reductions in therapy can be evaluated with the goal of maintaining favorable outcome while reducing long-term morbidity. However, the prognostic significance of the recurring genomic lesions for some other cancers remains to be defined.

A key finding from genomic studies is the extent to which the molecular characteristics of childhood cancers correlate with their tissue (cell) of origin. As with most adult cancers, mutations in childhood cancers do not arise at random, but rather are linked in specific constellations to disease categories. A few examples include the following:

  • The presence of H3.3 and H3.1 K27 mutations almost exclusively among pediatric midline high-grade gliomas.
  • The loss of SMARCB1 in rhabdoid tumors.
  • The presence of RELA translocations in supratentorial ependymomas.
  • The presence of specific fusion proteins in different pediatric sarcomas.

Another theme across multiple childhood cancers is the contribution of mutations of genes involved in normal development of the tissue of origin of the cancer and the contribution of genes involved in epigenomic regulation.

Structural variations play an important role for many childhood cancers. Translocations resulting in oncogenic fusion genes or overexpression of oncogenes play a central role, particularly for the leukemias and sarcomas. However, for other childhood cancers that are primarily characterized by structural variations, functional fusion genes are not produced. Mechanisms by which these recurring structural variations have oncogenic effects have been identified for osteosarcoma (translocations confined to the first intron of TP53) and medulloblastoma (structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements leading to transcriptional activation [enhancer hijacking]).[1,2] However, the oncogenic mechanisms of action for recurring structural variations of other childhood cancers (e.g., the segmental chromosomal alterations in neuroblastoma) need to be elucidated.

Understanding of the contribution of germline mutations to childhood cancer etiology is being advanced by the application of whole-genome and exome sequencing to cohorts of children with cancer. Estimates for rates of pathogenic germline mutations approaching 10% have emerged from studies applying these sequencing methods to childhood cancer cohorts.[3,4,5] In some cases, the pathogenic germline mutations are clearly contributory to the patient's cancer (e.g., TP53 mutations arising in the context of Li-Fraumeni syndrome), whereas in other cases the contribution of the germline mutation to the patient's cancer is less clear (e.g., mutations in adult cancer predisposition genes such as BRCA1 and BRCA2 that have an undefined role in childhood cancer predisposition).[4,5] The frequency of germline mutations varies by tumor type (e.g., lower for neuroblastoma and higher for osteosarcoma),[5] and many of the identified germline mutations fit into known predisposition syndromes (e.g., DICER1 for pleuropulmonary blastoma, SMARCB1 and SMARCA4 for rhabdoid tumor and small cell ovarian cancer, TP53 for adrenocortical carcinoma and Li-Fraumeni syndrome cancers, RB1 for retinoblastoma, etc.). The germline contribution to the development of specific cancers is discussed in the disease-specific sections that follow.

Each section of this document is meant to provide readers with a brief summary of current knowledge about the genomic landscape of specific childhood cancers, an understanding that is critical in considering how to apply precision medicine concepts to childhood cancers.

References:

  1. Northcott PA, Lee C, Zichner T, et al.: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511 (7510): 428-34, 2014.
  2. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014.
  3. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015.
  4. Parsons DW, Roy A, Yang Y, et al.: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. JAMA Oncol : , 2016.
  5. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015.

Leukemias

Acute Lymphoblastic Leukemia (ALL)

The genomics of childhood ALL has been extensively investigated and multiple distinctive subtypes based on cytogenetic and molecular characterizations have been defined, each with its own pattern of clinical and prognostic characteristics.[1] Figure 1 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.[1]
Pie chart showing subclassification of childhood ALL.
Figure 1. Subclassification of childhood ALL. Blue wedges refer to B-progenitor ALL, yellow to recently identified subtypes of B-ALL, and red wedges to T-lineage ALL.

The genomic landscape of B-precursor ALL is typified by a range of genomic alterations that disrupt normal B-cell development and in some cases by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3-PBX1 and ETV6-RUNX1), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[2]

The genomic alterations in B-precursor ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3-PBX1 and ETV6-RUNX1, and MLL (KMT2A)-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:

  • IKZF1 deletions and mutations are most commonly observed within cases of Philadelphia chromosome–positive (Ph+) ALL and Ph-like ALL.[3,4]
  • Intragenic ERG deletions occur within a distinctive subtype characterized by this alteration and lacking other recurring cytogenetic alterations associated with pediatric B-precursor ALL.[5,6,7]
  • TP53 mutations occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes, and the TP53 mutations in these patients are often germline.[8]TP53 mutations are uncommon in other patients with B-precursor ALL.

Activating point mutations in kinase genes are uncommon in high-risk B-precursor ALL, and JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome ALL.[4,9,10] Several kinase genes and cytokine receptor genes are activated by translocation as described below in the discussion of Ph-positive ALL and Ph-like ALL. FLT3 mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and MLL (KMT2A)-rearranged ALL, and are rare in other subtypes.[11]

Understanding of the genomics of B-precursor ALL at relapse is less advanced than understanding of ALL genomics at diagnosis. Childhood ALL is often polyclonal at diagnosis and under the selective influence of therapy, some clones may be extinguished and new clones with distinctive genomic profiles may arise.[12] Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-precursor ALL with early relapse that were evaluated for this mutation.[12,13]NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to 6-mercaptopurine and thioguanine.[13] Another gene that is found mutated only at relapse is PRSP1, a gene involved purine biosynthesis.[14] Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[12,15] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.

Specific genomic and chromosomal alterations are provided below, with a focus on their prognostic significance.

A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-precursor ALL. Some chromosomal abnormalities are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the ETV6-RUNX1 fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)), rearrangements of the MLL gene (chromosome 11q23), and intrachromosomal amplification of the AML1 gene (iAMP21).[16]

Chromosomal abnormalities in childhood B-precursor ALL, many of which have prognostic significance and some of which are used for treatment allocation, include the following:

  1. Chromosome number
    • High hyperdiploidy

      High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in 20% to 25% of cases of precursor B-cell ALL, but very rarely in cases of T-cell ALL.[17] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy. High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is itself an independent favorable prognostic factor.[17,18,19] Within the hyperdiploid range of 51 to 66 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[19] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[20] which may explain the favorable outcome commonly observed in these cases.

      While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[21,22]

      Patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have been shown to have a particularly favorable outcome as demonstrated by both Pediatric Oncology Group (POG) and Children's Cancer Group analyses of NCI standard-risk ALL.[23] POG data suggest that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[24]

      Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified based on the prognostic significance of the translocation. For instance, in one study, 8% of patients with the Philadelphia chromosome (t(9;22)) also had high hyperdiploidy,[25] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-Ph+ high hyperdiploid patients.

      Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[26] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes. These patients have an unfavorable outcome, similar to those with hypodiploidy.[26]

      Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[27] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6-RUNX1 fusion.[27,28,29] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[27,29]

      The genomic landscape of hyperdiploid ALL is represented by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL.[30]

    • Hypodiploidy (<44 chromosomes)

      Precursor B-cell ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying based on modal chromosome number into the following four groups:[26]

      • Near-haploid: 24 to 29 chromosomes (n = 46).
      • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
      • High-hypodiploid: 40 to 43 chromosomes (n = 13).
      • Near-diploid: 44 chromosomes (n = 54).

      Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[26,31] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[26]

      The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[8] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[32] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[8]

  2. Chromosomal translocations
    • ETV6-RUNX1 (t(12;21) cryptic translocation, formerly known as TEL-AML1)

      Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 can be detected in 20% to 25% of cases of B-precursor ALL but is rarely observed in T-cell ALL.[28] The t(12;21) occurs most commonly in children aged 2 to 9 years.[33,34] Hispanic children with ALL have a lower incidence of t(12;21) than do white children.[35]

      Reports generally indicate favorable event-free survival (EFS) and overall survival (OS) in children with the ETV6-RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[36,37,38,39,40]

      • Early response to treatment.
      • NCI risk category (age and WBC count at diagnosis).
      • Treatment regimen.

      In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6-RUNX1, to be independent prognostic factors.[36] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6-RUNX1 fusion.[40,41] There is a higher frequency of late relapses in patients with ETV6-RUNX1 fusion compared with other B-precursor ALL.[36,42] Patients with the ETV6-RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[43] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[44] Some relapses in patients with t(12;21) may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6-RUNX1 translocation).[45,46]

    • Philadelphia chromosome (t(9;22) translocation)

      The Philadelphia chromosome t(9;22) is present in approximately 3% of children with ALL and leads to production of a BCR-ABL1 fusion protein with tyrosine kinase activity (refer to Figure 2).


      Philadelphia chromosome; three-panel drawing shows a piece of chromosome 9 and a piece of chromosome 22 breaking off and trading places, creating a changed chromosome 22 called the Philadelphia chromosome. In the left panel, the drawing shows a normal chromosome 9 with the abl gene and a normal chromosome 22 with the bcr gene. In the center panel, the drawing shows chromosome 9 breaking apart in the abl gene and chromosome 22 breaking apart below the bcr gene. In the right panel, the drawing shows chromosome 9 with the piece from chromosome 22 attached and chromosome 22 with the piece from chromosome 9 containing part of the abl gene attached. The changed chromosome 22 with bcr-abl gene is called the Philadelphia chromosome.
      Figure 2. The Philadelphia chromosome is a translocation between the ABL-1 oncogene (on the long arm of chromosome 9) and the breakpoint cluster region (BCR) (on the long arm of chromosome 22), resulting in the fusion gene BCR-ABL1. BCR-ABL encodes an oncogenic protein with tyrosine kinase activity.

      This subtype of ALL is more common in older children with precursor B-cell ALL and high WBC count.

      Historically, the Philadelphia chromosome t(9;22) was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[25,47,48,49] Inhibitors of the BCR-ABL tyrosine kinase, such as imatinib mesylate, are effective in patients with Ph+ ALL.[50] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% ± 12%, which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era.[50,51,52]

    • MLL translocations

      Translocations involving the MLL (11q23) gene occur in up to 5% of childhood ALL cases and are generally associated with an increased risk of treatment failure.[53,54,55,56] The t(4;11) translocation is the most common translocation involving the MLL gene in children with ALL and occurs in approximately 2% of cases.[54]

      Patients with the t(4;11) translocation are usually infants with high WBC counts; they are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[57] While both infants and adults with the t(4;11) translocation are at high risk of treatment failure, children with the t(4;11) translocation appear to have a better outcome than either infants or adults.[53,54] Irrespective of the type of MLL gene rearrangement, infants with leukemia cells that have MLL gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have an MLL gene rearrangement.[53,54] Whole-genome sequencing has determined that cases of infant ALL with MLL gene rearrangements have few additional genomic alterations, none of which have clear clinical significance.[11] Deletion of the MLL gene has not been associated with an adverse prognosis.[58]

      Of interest, the t(11;19) translocation involving MLL and MLLT1/ENL occurs in approximately 1% of ALL cases and occurs in both early B-lineage and T-cell ALL.[59] Outcome for infants with the t(11;19) translocation is poor, but outcome appears relatively favorable in older children with T-cell ALL and the t(11;19) translocation.[59]

    • Translocations involving TCF3: TCF3-PBX1 (E2A-PBX1; t(1;19) translocation) and TCF3-HLF (t(17;19) translocation)

      The t(1;19) translocation occurs in approximately 5% of childhood ALL cases and involves fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1.[60,61] The t(1;19) translocation may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B ALL immunophenotype (cytoplasmic Ig positive).[62] Black children are more likely than white children to have pre-B ALL with the t(1;19).[63]

      The t(1;19) translocation had been associated with inferior outcome in the context of antimetabolite-based therapy,[64] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[61,65] However, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) on which all patients were treated without cranial radiation, patients with the t(1;19) translocation had an overall outcome comparable to children lacking this translocation, with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[66,67]

      The t(17;19) translocation resulting in the TCF3-HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3-HLF fusion is associated at diagnosis with disseminated intravascular coagulation and with hypercalcemia. Outcome is very poor for children with the t(17;19) translocation, with a literature review noting mortality for 20 of 21 cases reported.[68] In addition to the TCF3-HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).[62]

  3. Other genomic alterations

    Numerous new genetic lesions have been discovered by various array comparative hybridization and next-generation sequencing methods. Appreciation of these submicroscopic genomic abnormalities and mutations is redefining the subclassification of ALL:[5,69,70,71,72,73,74]

    • Intrachromosomal amplification of chromosome 21 (iAMP21): iAMP21 with multiple extra copies of the RUNX1 (AML1) gene occurs in approximately 2% of precursor B-cell ALL cases and is associated with older age (median, approximately 10 years), presenting WBC of less than 50 × 109 /l, a slight female preponderance, and high end-induction MRD.[75,76,77] The United Kingdom–ALL clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS, 29%).[16] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS, 78%).[76] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS, 73% vs 80%).[75] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[75] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance.[77]
    • IKZF1 deletions: IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of precursor B-cell ALL cases. Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore, more common among NCI high-risk patients compared with NCI standard-risk patients.[2,78,79] A high proportion of BCR-ABL1 cases have a deletion of IKZF1,[3,78] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[80]IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in Philadelphia chromosome–like (Ph-like) ALL (see below).[5,78,81]

      Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome on multivariate analyses.[5,78,81,82,83,84,85,86,87]; [88][Level of evidence: 2Di]; [79][Level of evidence: 2Dii] The prognostic impact of an IKZF1 deletion is not uniform across ALL biological subtypes, as illustrated by the favorable outcome for patients with both the IKZF1 deletion and the ERG deletion.[5,6,7,79]

    • ERG deletion: Approximately 4% of pediatric B-precursor ALL patients have a focal intragenic deletion in ERG, resulting in production of a truncated ERG protein.[5,6,7] Patients with ERG deletion are significantly older than are other patients with pediatric B-precursor ALL; 40% of them show aberrant CD2 expression, and approximately 40% have the IKZF1 deletion. The ERG deletion connotes an excellent prognosis, with OS exceeding 90%; even when the IZKF1 deletion is present, prognosis remains highly favorable.[5,6,7,79]
    • Ph-like ALL (BCR-ABL-like): BCR-ABL1–negative patients with a gene expression profile similar to BCR-ABL1–positive patients have been referred to as Ph-like ALL or BCR-ABL–like.[81,82] This occurs in 10% to 15% of pediatric ALL patients, increasing in frequency with age, and has been associated with a poor prognosis and with IKZF1 deletion/mutation.[9,73,81,82,86] The results of one study of 40 patients with Ph–like ALL suggested that the adverse prognostic significance of this subtype may be abrogated when patients are treated with risk-directed therapy based on MRD levels.[89][Level of evidence: 2A]

      The hallmark of this entity is activated kinase signaling, with 50% containing CRLF2 genomic alterations [90] and 25% containing concomitant JAK mutations.[91] Additional information about Ph-like ALL cases with CRLF2 genomic alterations is provided below.

      Many of the remaining cases of Ph-like ALL have been noted to have a series of translocations with a common theme of involvement of either ABL1, JAK2, PDGFRB, or EPOR.[73] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[73] suggesting potential therapeutic strategies for these patients. Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in Ph–like ALL cases.[9]

    • CRLF2 and JAK mutations: Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-precursor ALL and they represent approximately 50% of cases of Ph-like ALL.[92,93] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IgH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8-CRLF2 fusion.[9,90,92,93]CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions and JAK mutations;[9,78,90,91,93] they are also more common in children with Down syndrome.[93] Point mutations in kinase genes other than JAK1 and JAK2 are uncommon in CRLF2-overexpressing cases.[9]

      Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance on univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[71,90,92,93,94] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR-ABL-like expression signatures were associated with unfavorable outcome.[86] There is also controversy about whether the prognostic significance of CRLF2 abnormalities should be analyzed based on CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[71,94]

  4. Gene polymorphisms in drug metabolic pathways

    A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[95,96,97] For example, patients with mutant phenotypes of thiopurine methyltransferase (TPMT, a gene involved in the metabolism of thiopurines, such as 6-mercaptopurine), appear to have more favorable outcomes,[98] although such patients may also be at higher risk of developing significant treatment-related toxicities, including myelosuppression and infection.[99,100] Patients with homozygosity for TPMT variants associated with low activity typically are treated with reduced doses of 6-mercaptopurine to avoid excessive toxicity.

    Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[101]

    Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of IL-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[102] Polymorphic variants involving the reduced folate carrier and methotrexate metabolism have been linked to toxicity and outcome.[103,104] While these associations suggest that individual variations in drug metabolism can affect outcome, few studies have attempted to adjust for these variations; whether individualized dose modification based on these findings will improve outcome is unknown.

(Refer to the PDQ summary on Childhood Acute Lymphoblastic Leukemia Treatment for information about the treatment of childhood ALL.)

Acute Myeloid Leukemia (AML)

Pediatric AML is typically a disease of recurring chromosomal alterations, with conventional cytogenetics detecting structural and numerical cytogenetic abnormalities in 70% to 80% of children with AML, while the recently recognized cryptic translocations (e.g., NUP98/NSD1, CBFA2T3/GLIS2, and NUP98/KDM5A) and mutations (e.g., CEBPA and NPM1) account for many of the remaining cases.[105,106]

Comprehensive molecular profiling of AML in pediatric and adult cases has characterized AML as a disease showing both commonalities and distinct differences between the age groups.[106,107,108]Figure 3 (A) illustrates the frequencies of recurring gene mutations in adult and pediatric AML, showing that some mutations are differentially present between pediatric and adults cases (e.g., IDH1 and DNMT3A mutations being much more common in adults than children).[106]Figure 3 (B) shows that common genomic alterations in adult AML (FLT3-ITD, NPM1, and CEBPA mutations) are uncommon in children younger than 5 years but increase in frequency with age.
Charts showing (A) prevalence of AML-associated mutations in pediatric versus adult AML and (B) age-based prevalence of common AML-associated mutations.
Figure 3. (A) Prevalence of AML-associated mutations in pediatric versus adult AML, demonstrating lower incidence of mutations in pediatric AML. Bordered panel shows 2 newly discovered mutations in adults that are absent in pediatric AML. (B) Age-based prevalence of common AML-associated mutations.

Figure 4 (A) shows the marked variation in MLL (KMT2A)-rearranged AML by age, with much higher frequencies for infants compared with older children and adults.[106] Normal karyotype AML and core-binding factor AML show an opposing pattern, with very low rates in infancy and with increasing rates in the first two decades of life. Figure 4 (B) shows specific cryptic translocations that occur primarily in children (NUP98/NSD1, CBFA2T3/GLIS2, and NUP98/KDM5A) and vary by age.[106]
Charts showing age-based prevalence of specific karyotypic (A) or cryptic (B) translocations in AML.
Figure 4. Age-based prevalence of specific karyotypic (A) or cryptic (B) translocations in AML.

The genomic landscape of pediatric AML cases can change from diagnosis to relapse, with mutations detectable at diagnosis dropping out at relapse and conversely with new mutations appearing at relapse. A key finding in a study of 20 cases for which sequencing data were available at diagnosis and relapse was that the variant allele frequency at diagnosis strongly correlated with persistence of mutations at relapse.[109] Approximately 90% of the diagnostic variants with variant allele frequency greater than 0.4 persisted to relapse compared with only 28% with variant allele frequency less than 0.2 (P < .001). This observation is consistent with previous results showing that presence of the FLT3-ITD mutation predicted for poor prognosis only when there was a high FLT3-ITD allelic ratio.

Chromosomal analyses of leukemia (using either conventional cytogenetic methods and/or molecular methods) should be performed on children with AML because chromosomal abnormalities are important diagnostic and prognostic markers.[110,111,112,113,114,115] Clonal chromosomal abnormalities have been identified in the blasts of about 75% of children with AML and are useful in defining subtypes with particular characteristics (e.g., t(8;21), t(15;17), inv(16), 11q23 abnormalities, t(1;22)). Leukemias with the chromosomal abnormalities t(8;21) and inv(16) are called core-binding factor leukemias; core-binding factor (a transcription factor involved in hematopoietic stem cell differentiation) is disrupted by each of these abnormalities.

A unifying concept for the role of specific mutations in AML is that mutations that promote proliferation (Type I) and mutations that block normal myeloid development (Type II) are required for full conversion of hematopoietic stem/precursor cells to malignancy.[116,117] Support for this conceptual construct comes from the observation that there is generally mutual exclusivity within each type of mutation, such that a single Type I and a single Type II mutation are present within each case. Further support comes from genetically engineered models of AML for which cooperative events rather than single mutations are required for leukemia development. Type I mutations are commonly in genes involved in growth factor signal transduction and include mutations in FLT3, KIT, NRAS, KRAS, and PTNP11.[118] Type II genomic alterations include the common translocations and mutations associated with favorable prognosis (t(8;21), inv(16), t(16;16), t(15;17), CEBPA, and NPM1). MLL rearrangements (translocations and partial tandem duplication) are also classified as Type II mutations.

Specific recurring cytogenetic and molecular abnormalities are briefly described below. The abnormalities are listed by those in clinical use that identify patients with favorable or unfavorable prognosis, followed by other abnormalities.

Molecular abnormalities associated with favorable prognosis include the following:

  • t(8;21) (RUNX1-RUNX1T1): In leukemias with t(8;21), the RUNX1(AML1) gene on chromosome 21 is fused with the RUNX1T1 (ETO) gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas.[119,120] Adults with t(8;21) have a more favorable prognosis than adults with other types of AML.[110,121] These children have a more favorable outcome compared with children with AML characterized by normal or complex karyotypes [110,122,123,124] with 5-year overall survival (OS) of 80% to 90%.[113,114] The t(8;21) translocation occurs in approximately 12% of children with AML.[113,114]
  • inv(16) (CBFB-MYH11): In leukemias with inv(16), the CBF beta gene (CBFB) at chromosome band 16q22 is fused with the MYH11 gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype.[125] Inv(16) confers a favorable prognosis for both adults and children with AML [110,122,123,124] with a 5-year OS of about 85%.[113,114] Inv(16) occurs in 7% to 9% of children with AML.[113,114]
  • t(15;17) (PML-RARA): AML with t(15;17) is invariably associated with APL, a distinct subtype of AML that is treated differently than other types of AML because of its marked sensitivity to the differentiating effects of all-trans retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML.[126] Other much less common translocations involving the retinoic acid receptor alpha can also result in APL (e.g., t(11;17)(q23;q21) involving the PLZF gene).[127] Identification of cases with the t(11;17)(q23;q21) is important because of their decreased sensitivity to all-trans retinoic acid.[126,127] APL represents about 7% of children with AML.[114,128]
  • Nucleophosmin (NPM1) mutations: NPM1 is a protein that has been linked to ribosomal protein assembly and transport as well as being a molecular chaperone involved in preventing protein aggregation in the nucleolus. Immunohistochemical methods can be used to accurately identify patients with NPM1 mutations by the demonstration of cytoplasmic localization of NPM.[129] Mutations in the NPM1 protein that diminish its nuclear localization are primarily associated with a subset of AML with a normal karyotype, absence of CD34 expression,[130] and an improved prognosis in the absence of FLT3-internal tandem duplication (ITD) mutations in adults and younger adults.[130,131,132,133,134,135]

    Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[117,136,137,138]NPM1 mutations are associated with a favorable prognosis in patients with AML characterized by a normal karyotype.[117,137,138] For the pediatric population, conflicting reports have been published regarding the prognostic significance of an NPM1 mutation when a FLT3-ITD mutation is also present, with one study reporting that an NPM1 mutation did not completely abrogate the poor prognosis associated with having a FLT3-ITD mutation,[137,139] but with other studies showing no impact of a FLT3-ITD mutation on the favorable prognosis associated with an NPM1 mutation.[117,138]

  • CEBPA mutations: Mutations in the CCAAT/Enhancer Binding Protein Alpha gene (CEBPA) occur in a subset of children and adults with cytogenetically normal AML. In adults younger than 60 years, approximately 15% of cytogenetically normal AML cases have mutations in CEBPA.[134,140] Outcome for adults with AML with CEBPA mutations appears to be relatively favorable and similar to that of patients with core-binding factor leukemias.[134,140] Studies in adults with AML have demonstrated that CEBPA double-mutant, but not single-allele mutant, AML was independently associated with a favorable prognosis.[141,142,143,144]

    CEBPA mutations occur in 5% to 8% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2; 70% to 80% of pediatric patients have double-mutant alleles, which is predictive of a significantly improved survival and similar to the effect observed in adult studies.[145,146] Although both double- and single-mutant alleles of CEBPA were associated with a favorable prognosis in children with AML in one large study,[145] a second study observed inferior outcome for patients with single CEBPA mutations.[146] However, very low numbers of children with single-allele mutants were included in these two studies (only 13 in toto), making a conclusion regarding the prognostic significance of single-allele CEBPA mutations in children premature.[145]

Molecular abnormalities associated with an unfavorable prognosis include the following:

  • Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7).[110,121,147] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[113,121,147,148,149,150]

    In the past, patients with del(7q) were also considered to be at high risk of treatment failure and data from adults with AML support a poor prognosis for both del(7q) and monosomy 7.[115] However, outcome for children with del(7q), but not monosomy 7, appears to be comparable to that of other children with AML.[114,150] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[110,150,151]

    Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are 4 years of age and younger.[152]

  • Chromosome 3 (inv(3)(q21;q26) or t(3;3)(q21;q26)) and EVI1 overexpression: The inv(3) and t(3;3) abnormalities involving the EVI1 gene located at chromosome 3q26 are associated with poor prognosis in adults with AML,[110,121,153] but are very uncommon in children (<1% of pediatric AML cases).[113,123,154]
  • FLT3 mutations: Presence of a FLT3-ITD mutation appears to be associated with poor prognosis in adults with AML,[155] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[156,157]FLT3-ITD mutations also convey a poor prognosis in children with AML.[139,158,159,160,161,162] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% for adults).[160,161,163] The prevalence of FLT3-ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98-NSD1 fusion gene, of which 80% to 90% have FLT3-ITD.[164,165] Approximately 15% of patients with FLT3-ITD have NUP98-NSD1, and patients with both FLT3-ITD and NUP98-NSD1 have a poorer prognosis than do patients with FLT3-ITD and without NUP98-NSD1.[165]

    For APL, FLT3-ITD and point mutations occur in 30% to 40% of children and adults.[156,159,160,166,167,168,169] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[159,168,170,171] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid and arsenic trioxide.[166,167,170,172,173]

    Activating point mutations of FLT3 have also been identified in both adults and children with AML, though the clinical significance of these mutations is not clearly defined.

Other molecular abnormalities observed in pediatric AML include the following:

  • MLL gene rearrangements: Translocations of chromosomal band 11q23 involving the MLL gene, including most AMLs secondary to epipodophyllotoxin,[174] are associated with monocytic differentiation (FAB M4 and M5). MLL rearrangements are also reported in 5% to 10% of FAB M7 (AMKL) patients.[175] The most common translocation, representing approximately 50% of MLL-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23) in which the MLL gene is fused with the MLLT3(AF9) gene.[176] An MLL gene rearrangement occurs in approximately 20% of children with AML.[113,114] However, more than 50 different fusion partners have been identified for the MLL gene in patients with AML. The median age for 11q23/MLL-rearranged cases in the pediatric AML setting is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years.[176] However, pediatric cases with t(6;11)(q27;q23) and t(11;17)(q23;q21) have significantly older median ages at presentation (12 years and 9 years, respectively).[176]

    Outcome for patients with de novo AML and MLL gene rearrangement is generally reported as being similar to that for other patients with AML.[110,113,176,177] However, as the MLL gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or MLL-rearranged AML.[176] For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/MLL-rearranged AML, showed a highly favorable outcome with 5-year EFS of 92%. While reports from single clinical trial groups have variably described more favorable prognosis for cases with t(9;11), in which the MLL gene is fused with the AF9 gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup.[110,113,176,178,179,180] An international collaboration evaluating pediatric AMKL observed that the presence of t(9;11), which was seen in approximately 5% of AMKL cases, was associated with an inferior outcome compared with other AMKL cases.[175]

    Several 11q23/MLL-rearranged AML subgroups appear to be associated with poor outcome. For example, cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS.[110,114,181] Some cases with the t(10;11) translocation have fusion of the MLL gene with the AF10-MLLT10 at 10p12, while others have fusion of MLL with ABI1 at 10p11.2.[182,183] The international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS in the 20% to 30% range.[176] Patients with t(6;11)(q27;q23) and with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS of 11% and 29%, respectively, in the international retrospective study.[176] A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with MLL translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.[184]

  • t(6;9) (DEK-NUP214): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[185,186] This subgroup of AML has been associated with a poor prognosis in adults with AML,[185,187,188] and occurs infrequently in children (less than 1% of AML cases). The median age of children with DEK-NUP214 AML is 10 to 11 years, and approximately 40% of pediatric patients have FLT3-ITD.[189,190] t(6;9) AML appears to be associated with a high risk of treatment failure in children, particularly for those not proceeding to allogeneic stem cell transplantation.[113,186,189,190]
  • t(1;22) (RBM15-MKL1): The t(1;22)(p13;q13) translocation is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[113,191,192,193] An international collaboration found that t(1;22)(p13;q13) was observed in 14% of children (51 of 372) with AMKL and evaluable cytogenetics.[175] Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than that for other children with AMKL.[175,194,195] The translocation is uncommon in children with Down syndrome who develop AMKL.[191,193] In leukemias with t(1;22), the RBM15 (OTT) gene on chromosome 1 is fused to the MKL1 (MAL) gene on chromosome 22.[196,197] Cases with detectable RBM15-MKL1 fusion transcripts in the absence of t(1;22) have also been reported.[193]

    Outcomes for children with AMKL vary between reported cooperative group trials, including the impact of t(1;22) on outcome. An international collaboration found that patients with t(1;22) had a 5-year EFS (54.5% ± 8.0%) and OS (58.2% ± 7.7%) similar to that of other children with AMKL.[175] Some studies have suggested that within the context of intensive chemotherapy and adequate supportive care, infants with t(1;22) can have a relatively favorable outcome that is superior to that of children with AMKL whose leukemia lacks t(1;22), with only 3 of 16 children with t(1;22) relapsing in two series; however, other studies have found the opposite in regard to outcome (5-year EFS, 38% ± 17% vs. 53% ± 6% in other AMKL patients; P = .039).[193,194,198,199]

  • t(8;16) (MYST3-CREBBP): The t(8;16) translocation fuses the MYST3 gene on chromosome 8p11 to CREBBP on chromosome 16p13. t(8;16) AML occurs rarely in children, and in an international BFM AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation.[200] Outcome for children with t(8;16) AML appears similar to other types of AML. A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[200,201,202,203,204,205,206] These observations suggest that a watch and wait policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.[200]
  • t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves ETV6 on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of MNX1 (HLXB9).[207] The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH.[208,209,210] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with MLL rearrangement, and is associated with a high risk of treatment failure.[113,114,117,208,209,211]
  • NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners.[212] In the pediatric AML setting, the two most common fusion genes are NUP98-NSD1 and NUP98-JARID1A, with the former observed in one report in approximately 15% of cytogenetically normal pediatric AML and the latter observed in approximately 10% of pediatric AMKL.[164,194] AML cases with either NUP98 fusion gene show high expression of HOXA and HOXB genes, indicative of a stem cell phenotype.[186,194]
    • NUP98-NSD1: The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[164,165,186,213,214,215,216] This alteration occurs in approximately 4% to 5% of pediatric AML cases.[164,186,215] The highest frequency in the pediatric population is in the 5- to 9-year age group (approximately 8%), with lower frequency in younger children (approximately 2% in children younger than 2 years). NUP98-NSD1 cases present with high WBC count (median, 147 × 109 /L in one study).[164,165] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[164,186,213] A high percentage of NUP98-NSD1 cases (80% to 90%) have FLT3-ITD.[164,165] A study that included 12 children with NUP98-NSD1 AML reported that although all patients achieved CR, presence of NUP98-NSD1 independently predicted for poor prognosis, and children with NUP98-NSD1 AML had a high risk of relapse, with a resulting 4-year EFS of approximately 10%.[164] In another study that included children (n = 38) and adults (n = 7) with NUP98-NSD1 AML, presence of both NUP98-NSD1 and FLT3-ITD independently predicted for poor prognosis; patients with both lesions had a low CR rate (approximately 30%) and a low 3-year EFS rate (approximately 15%).[165]
    • NUP98-JARID1A: NUP98-JARID1A is a recurrent cryptic translocation in pediatric AMKL, accounting for approximately 10% of AMKL cases and having a median age at presentation of approximately 2 years. Risk of treatment failure appears high for patients with NUP98-JARID1A, although the number of patients studied is small.[194]
  • CBFA2T3-GLIS2: CBFA2T3-GLIS2 is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) [217,218] that is present in approximately 2% of pediatric AML.[194,217,219,220] It occurs most frequently in non–Down syndrome AMKL (~15% of patients),[194] but also has been observed in other cytogenetically normal pediatric AML subtypes (~4% of patients).[219] It has been associated with an inferior outcome.[217,220]
  • RAS mutations: Although mutations in RAS have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown.[117,221,222,223] Mutations in NRAS are observed more commonly than KRAS mutations in pediatric AML cases.[117,118]RAS mutations occur with similar frequency for all Type II alteration subtypes with the exception of APL, for which RAS mutations are seldom observed.[117]
  • KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[117,118,224,225] The presence of activating KIT mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without KIT mutation.[225,226,227] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[224,228,229,230] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[231]
  • GATA1 mutations: GATA1 mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL.[232,233,234,235]GATA1 mutations are not observed in non-Down syndrome children with AMKL or in Down syndrome children with other types of leukemia.[234,235]GATA1 is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells.[236]GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[237]
  • WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[238,239,240,241] The WT1 mutation has been shown in some,[238,239,241] but not all,[240] studies to be an independent predictor of worse disease-free, event-free, and OS of adults. In children with AML, WT1 mutations are observed in approximately 10% of cases.[242,243] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[242,243] AML cases with NUP98-NSD1 are enriched for both FLT3-ITD and WT1 mutations.[164] In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1 mutation status is unclear because of its strong association with FLT3-ITD and its association with NUP98-NSD1.[164,242,243] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3-ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3-ITD had survival rates less than 20%.[242]
  • DNMT3A mutations: Mutations of the DNA cytosine methyltransferase gene (DNMT3A) have been identified in approximately 20% of adult AML patients, being virtually absent in patients with favorable cytogenetics but occurring in one-third of adult patients with intermediate-risk cytogenetics.[244] Mutations in this gene are independently associated with poor outcome.[244,245,246]DNMT3A mutations appear to be very uncommon in children.[108]
  • IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[247,248,249,250,251] and they are enriched in patients with NPM1 mutations.[248,249,252] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[253,254] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[252] Mutations in IDH1 and IDH2 are uncommon in pediatric AML, occurring in 0% to 4% of cases.[108,255,256,257,258,259] There is no indication of a negative prognostic effect for IDH1 and IDH2 mutations in children with AML.[255]

(Refer to the PDQ summary on Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment for information about the treatment of childhood AML.)

Juvenile Myelomonocytic Leukemia (JMML)

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway:[260,261]NF1, NRAS, KRAS, PTPN11, and CBL. In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 5).[260] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 and CBL mutations accounted for 8% and 11% of cases, respectively. Although mutations among these five genes are generally mutually exclusive, 10% to 17% of cases have mutations in two of these Ras pathway genes,[260,261] a finding that is associated with poorer prognosis.[260]

The mutation rate in JMML leukemia cells is very low, but additional mutations beyond those of the five Ras pathway genes described above are observed.[260,261] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1 was mutated in 7%–9% of cases).[260,261,262]JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[260,261,262] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 5).[260]


Chart showing alteration profiles in individual JMML cases.
Figure 5. Alteration profiles in individual JMML cases. Germline and somatically acquired alterations with recurring hits in the RAS pathway and PRC2 network are shown for 118 patients with JMML who underwent detailed genetic analysis. Blast excess was defined as a blast count ≥10% but <20% of nucleated cells in the bone marrow at diagnosis. Blast crisis was defined as a blast count ≥20% of nucleated cells in the bone marrow. NS, Noonan syndrome. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Caye A, Strullu M, Guidez F, et al.: Juvenile myelomonocytic leukemia displays mutations in components of the RAS pathway and the PRC2 network. Nat Genet 47 [11]: 1334-40, 2015), copyright (2015).

Clinical implications

General characteristics of leukemia cells provide both prognostic information and guidance regarding therapeutic opportunities for JMML:

  • Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[260,261] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[261] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[261] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[260]
  • RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[263,264] and there are no clinical data available.

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  221. Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990.
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  225. Schnittger S, Kohl TM, Haferlach T, et al.: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 (5): 1791-9, 2006.
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  228. Shih LY, Liang DC, Huang CF, et al.: Cooperating mutations of receptor tyrosine kinases and Ras genes in childhood core-binding factor acute myeloid leukemia and a comparative analysis on paired diagnosis and relapse samples. Leukemia 22 (2): 303-7, 2008.
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  230. Boissel N, Leroy H, Brethon B, et al.: Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 20 (6): 965-70, 2006.
  231. Pollard JA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood 115 (12): 2372-9, 2010.
  232. Groet J, McElwaine S, Spinelli M, et al.: Acquired mutations in GATA1 in neonates with Down's syndrome with transient myeloid disorder. Lancet 361 (9369): 1617-20, 2003.
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Non-Hodgkin Lymphoma

Mature B-cell Lymphoma

The mature B-cell lymphomas include Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.

Burkitt and Burkitt-like lymphoma

The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).[1]

Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the c-myc oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of c-myc, a gene involved in cellular proliferation.[2,3,4] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.[5]

The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.[6]

Cytogenetic evidence of c-myc rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[1] BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.[7]

Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia has a gene expression signature similar to Burkitt lymphoma/leukemia.[8,9] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[8,10]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Diffuse large B-cell lymphoma

The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).[11]

Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:

  • The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[5,12,13] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[14]
  • Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen adults.[12]
  • As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[8,10]
  • In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[10,15]
  • A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[16]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Primary mediastinal B-cell lymphoma

Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification.[17] These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.

Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:

  • Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.[17]
  • Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.

Primary mediastinal B-cell lymphoma is associated with distinctive chromosomal aberrations (gains in chromosomes 9p and 2p in regions that involve JAK2 and c-rel, respectively) [18,19] and commonly shows inactivation of SOCS1 by either mutation or gene deletion.[20,21] Primary mediastinal B-cell lymphoma has a distinctly different gene expression profile from diffuse large B-cell lymphoma, but its gene expression profile has features similar to those seen in Hodgkin lymphoma.[22,23]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Lymphoblastic Lymphoma

Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[2,24]

As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity in 6q16.[25,26]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

Anaplastic Large Cell Lymphoma

While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.[27]

All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations.[28] Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations.[28]

In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[29] Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease.[30] In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[31,32,33]

In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[32] The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.[33]

(Refer to the PDQ summary on Childhood Non-Hodgkin Lymphoma Treatment for information about the treatment of childhood non-Hodgkin lymphoma.)

References:

  1. Leoncini L, Raphael M, Stein H: Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 262-4.
  2. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996.
  3. Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003.
  4. Miles RR, Cairo MS, Satwani P, et al.: Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report. Br J Haematol 138 (4): 506-12, 2007.
  5. Gualco G, Weiss LM, Harrington WJ Jr, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009.
  6. Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 265-6.
  7. Masqué-Soler N, Szczepanowski M, Kohler CW, et al.: Clinical and pathological features of Burkitt lymphoma showing expression of BCL2--an analysis including gene expression in formalin-fixed paraffin-embedded tissue. Br J Haematol 171 (4): 501-8, 2015.
  8. Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008.
  9. Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006.
  10. Deffenbacher KE, Iqbal J, Sanger W, et al.: Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 119 (16): 3757-66, 2012.
  11. Stein H, Warnke RA, Chan WC: Diffuse large B-cell lymphoma (DLBCL), NOS. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 233-7.
  12. Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006.
  13. Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008.
  14. Klapper W, Kreuz M, Kohler CW, et al.: Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 119 (8): 1882-7, 2012.
  15. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009.
  16. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011.
  17. Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.
  18. Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005.
  19. Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011.
  20. Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005.
  21. Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005.
  22. Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003.
  23. Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003.
  24. Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000.
  25. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013.
  26. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008.
  27. Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008.
  28. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001.
  29. Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008.
  30. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008.
  31. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000.
  32. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011.
  33. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014.

Central Nervous System Tumors

Central nervous system (CNS) tumors include low-grade gliomas, high-grade gliomas, oligodendrogliomas, brain stem gliomas, CNS atypical teratoid/rhabdoid tumors, medulloblastomas, CNS primitive neuroectodermal tumors, and ependymomas.

Low-Grade Gliomas

Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.

BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549 gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[1,2,3,4,5] This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.[1,2,6,7,8,9,10]

Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas.[10] However, other factors such as p16 deletion and tumor location may modify the impact of the BRAF mutation on outcome.[11] Progression to high-grade glioma is rare for pediatric low-grade glioma with the BRAF-KIAA1549 fusion.[12]

BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[9,10]

Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative BRAF gene fusions, RAF1 rearrangements, RAS mutations, and BRAF V600E point mutations) are less commonly observed.[2,4,5,13]BRAF V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytoma cases.[14,15,16] One retrospective study of 53 children with gangliogliomas demonstrated BRAF V600E staining in approximately 40% of tumors. Five-year recurrence-free survival was worse in the V600E-mutated tumors (about 60%) than in tumors that did not stain for V600E (about 80%).[17] The frequency of the BRAF V600E mutation was significantly higher in pediatric low-grade glioma that transformed to high-grade glioma (8 of 18 cases) than was the frequency of mutation in cases that did not transform (10 of 167 cases).[12]

As with neurofibromatosis type 1 (NF1) deficiency in activating the ERK/MAPK pathway, activating BRAF genomic alterations are uncommon in pilocytic astrocytoma associated with NF1.[8]

Activating mutations in FGFR1, PTPN11, and in NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[18] In pediatric grade II diffuse astrocytomas, the most common alterations reported (up to 53% of tumors) are rearrangements in the MYB family of transcription factors.[19,20]

Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (TSC1/hamartin or TSC2/tuberin). Either of these mutations results in an overexpression of the mammalian target of rapamycin (mTOR) complex 1. These children are at risk of developing subependymal giant cell astrocytomas, cortical tubers, and subependymal nodules.

(Refer to the PDQ summary on Childhood Astrocytomas Treatment for information about the treatment of low-grade childhood astrocytomas.)

High-Grade Gliomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[21,22,23,24] Pediatric high-grade gliomas have PTEN and EGFR genomic alterations less frequently and PDGF/PDGFR genomic alterations and mutations in histone H3.3 genes more frequently than do adult tumors. Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult secondary glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have IDH1 and IDH2 mutations, the latter mutations are rarely observed in childhood glioblastoma multiforme tumors.[25,26,27]

Based on epigenetic patterns (DNA methylation), pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups with distinctive chromosome copy number gains/losses and gene mutations.[27]

Two subgroups have identifiable recurrent H3F3A mutations, suggesting disrupted epigenetic regulatory mechanisms, with one subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34). The subgroups are the following:

  • H3F3A mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brainstem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have TP53 mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of H3F3A K27 mutations.[28]
  • H3F3A mutation at G34: The second H3F3A mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have TP53 mutations and widespread hypomethylation across the whole genome.

The H3F3A K27 and G34 mutations appear to be unique to high-grade gliomas and have not been observed in other pediatric brain tumors.[29] Both mutations induce distinctive DNA methylation patterns compared with the patterns observed in IDH-mutated tumors, which occur in young adults.[25,26,27,29,30]

Other pediatric glioblastoma multiforme subgroups include the RTK PDGFRA and mesenchymal clusters, both of which occur over a wide age range, affecting both children and adults. The RTK PDGFRA and mesenchymal subtypes are predominantly composed of cortical tumors, with cerebellar glioblastoma multiforme tumors rarely observed; both subtypes have a poor prognosis.[27]

Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven (approximately 40%) of 18 patients with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 (57%) of 14 cases.[12]

(Refer to the PDQ summary on Childhood Astrocytomas Treatment for information about the treatment of high-grade childhood astrocytomas.)

Oligodendrogliomas

The molecular profile of pediatric patients with oligodendrogliomas rarely demonstrates deletions of 1p and 19q, as found in 40% to 80% of adult cases. Similarly, IDH1 mutations are also uncommon. When 1p19q codeletion or IDH1 mutations are present in pediatric oligodendroglioma, they are observed primarily in patients older than 15 years.[19,31,32] Like other diffuse pediatric low-grade gliomas, pediatric oligodendrogliomas were noted to have FGFR1 tyrosine kinase domain duplications (3 of 5 cases studied), with an MYB fusion gene observed in one of the two remaining cases.[19]

Brain Stem Gliomas (Diffuse Intrinsic Pontine Gliomas [DIPGs])

The genomic characteristics of DIPGs appear to differ from those of most other pediatric high-grade gliomas and from those of adult high-grade gliomas. A number of chromosomal and genomic abnormalities have been reported for DIPG, including the following:

  • Histone H3 genes: Approximately 80% of DIPG tumors have a mutation in a specific amino acid in the histone H3.1 (H3F3A) or H3.3 (HIST1H3B) genes.[26,33,34,35,36] These same mutations are observed in pediatric high-grade gliomas at other midline locations but are uncommon in cortical pediatric high-grade gliomas and in adult high-grade gliomas.[25,26,33,34,35,36]
  • Activin A receptor, type I (ACVR1) gene: Approximately 20% of DIPG cases have activating mutations in the ACVR1 gene, with most occurring concurrently with H3.3 mutations.[33,34,35,36] Germline mutations in ACVR1 cause the autosomal dominant syndrome fibrodysplasia ossificans progressiva (FOP), although there is no cancer predisposition in FOP.[37]
  • Receptor tyrosine kinase amplification: PDGFRA amplification occurs in approximately 30% of cases, with lower rates of amplification observed for some other receptor tyrosine kinases (e.g., MET and IGF1R).[38,39]
  • TP53 deletion: DIPG tumors commonly show deletion of the TP53 gene on chromosome 17p.[39] Additionally, TP53 is commonly mutated in DIPG tumors, particularly those with histone H3 gene mutations.[30,33,34,35,36] Aneuploidy is commonly observed in cases with TP53 mutations.[36]

The gene expression profile of DIPG differs from that of non–brain stem pediatric high-grade gliomas, further supporting a distinctive biology for this subset of pediatric gliomas.[39]

(Refer to the PDQ summary on Childhood Brain Stem Glioma Treatment for information about the treatment of childhood brain stem gliomas.)

Central Nervous System (CNS) Atypical Teratoid/Rhabdoid Tumors (AT/RT)

SMARCB1gene

AT/RT was the first primary pediatric brain tumor for which a candidate tumor suppressor gene, SMARCB1 (also known as INI1 and hSNF5), was identified.[40]SMARCB1 is genomically altered in the majority of rhabdoid tumors, including CNS, renal, and extrarenal rhabdoid malignancies.[40] Additional genomic alterations (mutations and gains/losses) in other genes are very uncommon in patients with SMARCB1-associated AT/RT, and there are no other genes that are recurrently mutated.[41,42,43]

SMARCB1 is a component of a switch (SWI) and sucrose non-fermenting (SNF) adenosine triphosphate–dependent chromatin-remodeling complex.[44] Rare familial cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 mutations have also been associated with germline mutations of SMARCA4/BRG1, another member of the SWI/SNF chromatin-remodeling complex.[45,46]

Despite the absence of recurring genomic alterations beyond SMARCB1 (and, more rarely, other SWI/SNF complex members), biologically distinctive subsets of AT/RT have been identified.[47,48] The following three distinctive subsets of AT/RT were identified through the use of DNA methylation arrays for 150 AT/RT tumors and gene expression arrays for 67 AT/RT tumors:[48]

  • AT/RT TYR: This subset represented approximately one-third of cases and was characterized by elevated expression of melanosomal markers such as TYR (the gene encoding tyrosinase). Cases in this subset were primarily infratentorial, with most presenting in children aged 0 to 1 years and showing chromosome 22q loss.
  • AT/RT SHH: This subset represented approximately 40% of cases and was characterized by elevated expression of genes in the sonic hedgehog (SHH) pathway (e.g., GLI2 and MYCN). Cases in this subset occurred with similar frequency in the supratentorium and infratentorium. While most presented before age 2 years, approximately one-third of cases presented between ages 2 and 5 years.
  • AT/RT MYC: This subset represented approximately one-fourth of cases and was characterized by elevated expression of MYC. AT/RT MYC cases tended to occur in the supratentorial compartment. While most AT/RT MYC cases occurred by age 5 years, AT/RT MYC represented the most common subset diagnosed at age 6 years and older. Focal deletions of SMARCB1 were the most common mechanism of SMARCB1 loss for this subset.

In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of AT/RT patients.[40,49] A study of 65 children with rhabdoid tumors found that 23 (35%) had germline mutations and/or deletions of SMARCB1.[50] Children with germline alterations in SMARCB1 presented at an earlier age than did sporadic cases (median age, approximately 5 months versus 18 months) and were more likely to present with multiple tumors.[50] One parent was found to be a carrier of the SMARCB1 germline abnormality in 7 of 22 evaluated cases showing germline alterations, with four of the carrier parents being unaffected by SMARCB1-associated cancers.[50] This indicates that AT/RT shows an autosomal dominant inheritance pattern with incomplete penetrance.

Gonadal mosaicism has also been observed, as evidenced by families in which multiple siblings are affected by AT/RT and have identical SMARCB1 alterations, but both parents lack a SMARCB1 mutation/deletion.[50,51] Screening children diagnosed with AT/RT for germline SMARCB1 mutations may provide useful information for counseling families on the genetic implications of their child's AT/RT diagnosis.[50]

(Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment for information about the treatment of childhood CNS atypical teratoid/rhabdoid tumors.)

Medulloblastomas

Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67] Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes; however, it is likely that further subclassification will occur.[65,66,68]

The following four core subtypes of medulloblastoma have been identified:[65,66,69,70]

  • WNT medulloblastoma: WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway. WNT medulloblastoma shows a WNT signaling gene expression signature and beta-catenin nuclear staining. They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. They are infrequently metastasized at diagnosis. Genetically, these tumors have 6q loss (monosomy 6), CTNNB1 mutations, and activated WNT signaling; MYC overexpression may be seen occasionally.[71]

    The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region. WNT medulloblastomas are associated with a very good outcome, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 mutations.[67,72]

  • Sonic hedgehog (SHH) medulloblastoma: SHH tumors are medulloblastomas with aberrations in the SHH pathway. SHH medulloblastomas are characterized by chromosome 9q deletions; desmoplastic/nodular histology; and mutations in SHH pathway genes, including PTCH1, PTCH2, SMO, SUFU, and GLI2.

    SHH medulloblastomas show a bimodal age distribution and are observed primarily in children younger than 3 years and in older adolescence/adulthood. The tumors are believed to emanate from the external granular layer of the cerebellum.

    Prognosis for patients with SHH medulloblastoma appears to be negatively affected by other molecular genetic changes, such as chromosome 17p loss, chromosome 3q gain, chromothripsis, p53 amplification, TP53 mutation, and the finding of large cell/anaplastic histology.[66,73] The outcome for patients with SHH medulloblastoma is relatively favorable, primarily in children younger than 3 years and in adults. This is likely because of the type of mutation present in the SHH pathway, given that patients with mutations upstream of the SHH signaling pathway, such as PTCH1, PTCH2, and SUFU, have a more favorable prognosis than do patients with downstream genomic aberrations, such as GLI2 and MYCN amplification.[74,75] Overall outcome in adolescents and young adults with SHH medulloblastoma is not different from that seen in patients with non-WNT pathway–activated tumors, except for patients with TP53 mutations and downstream SHH pathway mutations. Patients with unfavorable molecular findings have an unfavorable prognosis, with less than 50% of patients surviving after conventional treatment.[69,73,74,75,76]

  • Group 3 medulloblastoma: Histology of group 3 medulloblastoma is either classic or large cell/anaplastic; these tumors are frequently metastasized at the time of diagnosis. A variety of different genomic aberrations have been noted in these tumors, including the presence of i17q and, most characteristically, MYC amplification.

    Group 3 medulloblastomas occur throughout childhood and may occur in infants. Males outnumber females in a 2:1 ratio in this medulloblastoma subtype. Patients with group 3 medulloblastomas have a variable prognosis. Patients with MYC amplification or MYC overexpression have a poor prognosis, with less than 50% of these patients surviving 5 years after diagnosis. This poor prognosis is especially true in children younger than 4 years at diagnosis.[69] However, patients with group 3 medulloblastoma without MYC amplification or MYC overexpression who are older than 3 years have a prognosis similar to that of most patients with medulloblastoma, with a 5-year PFS rate higher than 70%.[76]

  • Group 4 medulloblastoma: Group 4 medulloblastomas are either classic or large cell/anaplastic tumors. Metastasis at diagnosis is common, but not as frequent as is seen in group 3 medulloblastomas. Molecularly, the medulloblastomas can have a CDK6 amplification, MYCN amplification, and most characteristically, an i17q abnormality.

    Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. They also predominate in males. The prognosis is better than group 3 medulloblastoma but not as good as WNT medulloblastoma. Prognosis for group 4 medulloblastoma patients is affected by additional factors such as the presence of metastatic disease and chromosome 17p loss.[65,66]

Optimal ways of identifying the four core medulloblastoma subtypes for clinical use is under active study, and both immunohistochemical methods and methods based on gene expression analysis are under development.[72,77] The classification of medulloblastoma into the four major subtypes will be altered in the future.[78,79] Further subdivision within subgroups based on molecular characteristics is likely as each of the subgroups is further molecularly dissected, although there is no consensus regarding an alternative classification.[65,68,75]

Whether the classification for adults with medulloblastoma has similar predictive ability in children is unknown.[66,69] In one study of adult medulloblastoma, MYC oncogene amplifications were rarely observed, and tumors with 6q deletion and WNT activation (as identified by nuclear beta-catenin staining) did not share the excellent prognosis seen in pediatric medulloblastomas, although another study did confirm an excellent prognosis for WNT-activated tumors in adults.[66,69]

(Refer to the PDQ summary on Childhood Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood medulloblastoma.)

CNS Primitive Neuroectodermal Tumors (PNET)

This section describes the genomic characteristics of central nervous system primitive neuroectodermal tumors (CNS PNETs) and pineoblastoma.

CNS PNET

CNS PNETs are a heterogeneous group of embryonal tumors with aggressive clinical behavior. Their microscopic appearance ranges from poorly differentiated to showing areas of differentiation along neuronal, astrocytic, or ependymal lines.[80] While initially the concept of CNS PNET was to align this category with medulloblastoma as a cerebellar PNET,[81] it is now clear that CNS PNETs are biologically distinctive from medulloblastoma. The 2007 World Health Organization (WHO) Classification of Tumors of the CNS categorized CNS PNETs into five subsets—supratentorial PNET not otherwise specified, CNS neuroblastomas, CNS ganglioneuroblastomas, medulloepithelioma, and ependymoblastoma.[80] As described below, the application of genomic characterization to these cancers has identified unrecognized commonalities between subtypes previously considered distinctive and has also identified biologic heterogeneity within subtypes.

A study applying unsupervised clustering of DNA methylation patterns for 323 CNS PNETs found that approximately one-half of these tumors diagnosed as CNS PNETs showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade glioma, atypical teratoid/rhabdoid tumor).[82] This observation highlights the utility of molecular characterization to assign this class of tumors to their appropriate biology-based diagnosis.

Among the same collection of 323 tumors diagnosed as CNS PNETs, molecular characterization identified genomically and biologically distinctive subtypes, including the following:

  • Embryonal tumors with multilayered rosettes (ETMR): Representing 11% of the 323 cases, this subtype combines embryonal rosette-forming neuroepithelial brain tumors that were previously categorized as either embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, or medulloepithelioma.[82,83] ETMRs arise in young children (median age at diagnosis, 2–3 years) and show a highly aggressive clinical course, with a median PFS of less than 1 year and few long-term survivors.[83]

    ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[83,84,85] This gene fusion puts expression of C19MC under control of the TTYH1 promoter, leading to high-level aberrant expression of the microRNAs within the cluster.

  • CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2): Representing 14% of the 323 cases, this subtype is characterized by genomic alterations that lead to increased expression of the transcription factor FOXR2.[82] CNS NB-FOXR2 is primarily observed in children younger than 10 years, and the histology of these tumors is typically that of CNS neuroblastoma or CNS ganglioneuroblastoma (as described in the 2007 WHO classification).[82] There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple FOXR2 partners identified.[82]
  • CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC): Representing 4% of the 323 cases, this subtype is characterized by genomic alterations affecting CIC (located on chromosome 19q13.2), with fusion to NUTM1 being identified in several cases tested.[82]CIC gene fusions are also identified in extra-CNS Ewing-like sarcomas, and the gene expression signature of CNS EFT-CIC tumors is similar to that of these sarcomas.[82] CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology.[82]
  • CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1): Representing 3% of the 323 cases, this subtype is characterized by gene fusions involving MN1 (located on chromosome 22q12.3), with fusion partners including BEND2 and CXXC5.[82] This subtype shows a striking female predominance and tends to occur in the second decade of life.[82] This subtype contained most cases carrying a diagnosis of astroblastoma as per the 2007 WHO classification scheme.[82]
  • CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR): Representing 3% of the 323 cases, this subtype is characterized by internal tandem duplications of BCOR,[82] a genomic alteration that is also found in clear cell sarcoma of the kidney.[86,87] While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur.[82]

Pineoblastoma

Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the WHO as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those utilized for embryonal tumors, the previous convention of including pineoblastoma with the CNS PNETs is followed here. Pineoblastoma is associated with germline mutations in both the retinoblastoma (RB1) gene and in DICER1, as described below:

  • Pineoblastoma is associated with germline mutations in RB1, with the term trilateral retinoblastoma used to refer to ocular retinoblastoma in combination with a histologically similar brain tumor generally arising in the pineal gland or other midline structures. Historically, intracranial tumors have been reported in 5% to 15% of children with heritable retinoblastoma.[88] Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.[89,90,91]
  • Germline DICER1 mutations have also been reported in patients with pineoblastoma.[92] Among 18 patients with pineoblastoma, three patients with DICER1 germline mutations were identified, and an additional three patients known to be carriers of germline DICER1 mutations developed pineoblastoma.[92] The DICER1 mutations in patients with pineoblastoma are loss-of-function mutations that appear to be distinct from the mutations observed in DICER1 syndrome–related tumors such as pleuropulmonary blastoma.[92]

(Refer to the PDQ summary on Childhood Central Nervous System Embryonal Tumors Treatment for information about the treatment of childhood PNETs.)

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Hepatoblastoma and Hepatocellular Carcinoma

Genomic abnormalities related to hepatoblastoma include the following:

  • Hepatoblastoma mutation frequency, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1,2,3]
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in 70% of cases.[1] Rare causes of WNT pathway activation include mutations in AXIN1, AXIN2, and APC (APC seen only in cases associated with familial adenomatosis polyposis coli).[4]
  • The frequency of NFE2L2 mutations in hepatoblastoma specimens was reported to be 4 (7%) of 62 tumors in one study [2] and 5 (10%) of 51 specimens in another study.[1] Similar mutations have been found in many types of cancer including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
  • Somatic mutations were identified in other genes related to regulation of oxidative stress, including inactivating mutations in the thioredoxin-domain containing genes, TXNDC15 and TXNDC16.[2]
  • Figure 6 shows the distribution of CTNNB1, NFE2L2, and TERT mutations for hepatoblastoma.[1]
    Chart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.
    Figure 6. Mutational status and functional relevance of NFE2L2 in hepatoblastoma. Clinicopathological characteristics and the mutational status of the CTNNB1, APC, and NFE2L2 genes, as well as the TERT promoter region are color-coded and depicted in rows for each tumor of our cohort of 43 hepatoblastoma (HB) patients and four transitional liver cell tumour (TLCT) patients and 4 HB cell lines. Reprinted from Journal of Hepatology, Volume 61 (Issue 6), Melanie Eichenmüller, Franziska Trippel, Michaela Kreuder, Alexander Beck, Thomas Schwarzmayr, Beate Häberle, Stefano Cairo, Ivo Leuschner, Dietrich von Schweinitz, Tim M. Strom, Roland Kappler, The genomic landscape of hepatoblastoma and their progenies with HCC-like features, Pages 1312–1320, Copyright 2014, with permission from Elsevier.

Genomic abnormalities related to hepatocellular carcinoma include the following:

  • A first case of pediatric hepatocellular carcinoma was analyzed by whole-exome sequencing, which showed a higher mutation rate (53 variants) and the coexistence of CTNNB1 and NFE2L2 mutations.[5]
  • Fibrolamellar hepatocellular carcinoma, a rare subtype of hepatocellular carcinoma observed in older children, is characterized by an approximately 400 kB deletion on chromosome 19 that results in production of a chimeric RNA coding for a protein containing the amino-terminal domain of DNAJB1, a homolog of the molecular chaperone DNAJ, fused in frame with PRKACA, the catalytic domain of protein kinase A.[6]
  • A rare, more aggressive subtype of childhood liver cancer (hepatocellular carcinoma, not otherwise specified, also termed transitional liver cell tumor) occurs in older children, and it has clinical and histopathological findings of both hepatoblastoma and hepatocellular carcinoma. TERT mutations were observed in two of four cases tested.[1]TERT mutations are also commonly observed in adults with hepatocellular carcinoma.[7]

(Refer to the PDQ summary on Childhood Liver Cancer Treatment for information about the treatment of liver cancer.)

References:

  1. Eichenmüller M, Trippel F, Kreuder M, et al.: The genomic landscape of hepatoblastoma and their progenies with HCC-like features. J Hepatol 61 (6): 1312-20, 2014.
  2. Trevino LR, Wheeler DA, Finegold MJ, et al.: Exome sequencing of hepatoblastoma reveals recurrent mutations in NFE2L2. [Abstract] Cancer Res 73 (8 Suppl): A-4592, 2013. Also available online. Last accessed August 05, 2016.
  3. Jia D, Dong R, Jing Y, et al.: Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex. Hepatology 60 (5): 1686-96, 2014.
  4. Hiyama E, Kurihara S, Onitake Y: Integrated exome analysis in childhood hepatoblastoma: Biological approach for next clinical trial designs. [Abstract] Cancer Res 74 (19 Suppl): A-5188, 2014.
  5. Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.: Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations. J Hepatol 61 (5): 1178-83, 2014.
  6. Honeyman JN, Simon EP, Robine N, et al.: Detection of a recurrent DNAJB1-PRKACA chimeric transcript in fibrolamellar hepatocellular carcinoma. Science 343 (6174): 1010-4, 2014.
  7. Nault JC, Mallet M, Pilati C, et al.: High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat Commun 4: 2218, 2013.

Sarcomas

Ewing Sarcoma

The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (refer to Table 1).[1] The EWSR1 gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins.[2] The FLI1 gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the EWSR1 gene is juxtaposed with the carboxy terminus of the STS family gene. In most cases (90%), the carboxy terminus is provided by FLI1, a member of the family of transcription factor genes located on chromosome 11 band q24. Other family members that may combine with the EWSR1 gene are ERG, ETV1, ETV4 (also termed E1AF), and FEV.[3] Rarely, TLS, another TET family member, can substitute for EWSR1.[4] Finally, there are a few rare cases in which EWSR1 has translocated with partners that are not members of the ETS family of oncogenes. The significance of these alternate partners is not known.

Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[5]

Three papers have described the genomic landscape of Ewing sarcoma and all show that these tumors have a relatively silent genome, with a paucity of mutations in pathways that might be amenable to treatment with novel targeted therapies.[6,7,8] These papers also identified mutations in STAG2, a member of the cohesin complex, in about 15% to 20% of the cases, and the presence of these mutations was associated with advanced-stage disease. CDKN2A deletions were noted in 12% to 22% of cases. Finally, TP53 mutations were identified in about 6% to 7% of cases and the coexistence of STAG2 and TP53 mutations is associated with a poor clinical outcome.[6,7,8]

Figure 7 below from a discovery cohort (n = 99) highlights the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of CDKN2A deletion and STAG2 mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[6]


Chart showing a comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information.
Figure 7. A comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information. Key clinical characteristics are indicated, including primary site, type of tissue, and metastatic status at diagnosis, follow-up, and last news. Below is the consistency of detection of gene fusions by RT-PCR and whole-genome sequencing (WGS). The numbers of structural variants (SV) and single-nucleotide variants (SNV) as well as indels are reported in grayscale. The presence of the main copy-number changes, chr 1q gain, chr 16 loss, chr 8 gain, chr 12 gain, and interstitial CDKN2A deletion is indicated. Listed last are the most significant mutations and their types. For gene mutations, "others" refers to: duplication of exon 22 leading to frameshift (STAG2), deletion of exon 2 to 11 (BCOR), and deletion of exons 1 to 6 (ZMYM3). Reprinted from Cancer Discovery, Copyright 2014, 4 (11), 1342–53, Tirode F, Surdez D, Ma X, et al., Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 mutations, with permission from AACR.

Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWS gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[9] This test result must be considered with caution, however. Ewing sarcomas that utilize the TLS translocations will have negative tests because the EWSR1 gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different ETS family members with EWSR1, such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a EWS fluorescence in situ hybridization split apart probe.

Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the EWSR1 gene have been analyzed and translocations have been identified. These include BCOR-CCNB3, CIC-DUX4, and CIC-FOX4.[10,11,12,13] The molecular profile of these tumors is different from the profile of EWS-FLI1 translocated Ewing sarcoma, and limited evidence suggests that they have a different clinical behavior. In almost all cases, the patients were treated with therapy designed for Ewing sarcoma on the basis of the histologic and immunohistologic similarity to Ewing sarcoma. There are too few cases associated with each translocation to determine whether the prognosis for these small round blue cell tumors is distinct from the prognosis of Ewing sarcoma of similar stage and site.[10,11,12,13]

A genome-wide association study identified a region on chromosome 10q21.3 associated with an increased risk of Ewing sarcoma.[14] Deep sequencing through this region identified a polymorphism in the EGR2 gene, which appears to cooperate with the gene product of the EWSR1-FLI1 fusion that is seen in most patients with Ewing sarcoma.[15] The polymorphism associated with the increased risk is found at a much higher frequency in whites than in blacks or Asians, possibly contributing to the epidemiology of the relative infrequency of Ewing sarcoma in the latter populations.

Table 1.EWSandTLSFusions and Translocations in Ewing Sarcoma
TET Family Partner Fusion With ETS-like Oncogene Partner Translocation Comment
a These partners are not members of theETSfamily of oncogenes.
EWS EWSR1-FLI1 t(11;22)(q24;q12) Most common; ~85% to 90% of cases
EWSR1-ERG t(21;22)(q22;q12) Second most common; ~10% of cases
EWSR1-ETV1 t(7;22)(p22;q12) Rare
EWSR1-ETV4 t(17;22)(q12;q12) Rare
EWSR1-FEV t(2;22)(q35;q12) Rare
EWSR1-NFATc2a t(20;22)(q13;q12) Rare
EWSR1-POU5F1a t(6;22)(p21;q12)  
EWSR1-SMARCA5a t(4;22)(q31;q12) Rare
EWSR1-ZSGa t(6;22)(p21;q12)  
EWSR1-SP3a t(2;22)(q31;q12) Rare
TLS(also calledFUS) TLS-ERG t(16;21)(p11;q22) Rare
TLS-FEV t(2;16)(q35;p11) Rare

(Refer to the PDQ summary on Ewing Sarcoma Treatment for information about the treatment of Ewing sarcoma.)

References:

  1. Delattre O, Zucman J, Melot T, et al.: The Ewing family of tumors--a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331 (5): 294-9, 1994.
  2. Urano F, Umezawa A, Yabe H, et al.: Molecular analysis of Ewing's sarcoma: another fusion gene, EWS-E1AF, available for diagnosis. Jpn J Cancer Res 89 (7): 703-11, 1998.
  3. Hattinger CM, Rumpler S, Strehl S, et al.: Prognostic impact of deletions at 1p36 and numerical aberrations in Ewing tumors. Genes Chromosomes Cancer 24 (3): 243-54, 1999.
  4. Sankar S, Lessnick SL: Promiscuous partnerships in Ewing's sarcoma. Cancer Genet 204 (7): 351-65, 2011.
  5. Roberts P, Burchill SA, Brownhill S, et al.: Ploidy and karyotype complexity are powerful prognostic indicators in the Ewing's sarcoma family of tumors: a study by the United Kingdom Cancer Cytogenetics and the Children's Cancer and Leukaemia Group. Genes Chromosomes Cancer 47 (3): 207-20, 2008.
  6. Tirode F, Surdez D, Ma X, et al.: Genomic landscape of Ewing sarcoma defines an aggressive subtype with co-association of STAG2 and TP53 mutations. Cancer Discov 4 (11): 1342-53, 2014.
  7. Crompton BD, Stewart C, Taylor-Weiner A, et al.: The genomic landscape of pediatric Ewing sarcoma. Cancer Discov 4 (11): 1326-41, 2014.
  8. Brohl AS, Solomon DA, Chang W, et al.: The genomic landscape of the Ewing Sarcoma family of tumors reveals recurrent STAG2 mutation. PLoS Genet 10 (7): e1004475, 2014.
  9. Monforte-Muñoz H, Lopez-Terrada D, Affendie H, et al.: Documentation of EWS gene rearrangements by fluorescence in-situ hybridization (FISH) in frozen sections of Ewing's sarcoma-peripheral primitive neuroectodermal tumor. Am J Surg Pathol 23 (3): 309-15, 1999.
  10. Pierron G, Tirode F, Lucchesi C, et al.: A new subtype of bone sarcoma defined by BCOR-CCNB3 gene fusion. Nat Genet 44 (4): 461-6, 2012.
  11. Specht K, Sung YS, Zhang L, et al.: Distinct transcriptional signature and immunoprofile of CIC-DUX4 fusion-positive round cell tumors compared to EWSR1-rearranged Ewing sarcomas: further evidence toward distinct pathologic entities. Genes Chromosomes Cancer 53 (7): 622-33, 2014.
  12. Sugita S, Arai Y, Tonooka A, et al.: A novel CIC-FOXO4 gene fusion in undifferentiated small round cell sarcoma: a genetically distinct variant of Ewing-like sarcoma. Am J Surg Pathol 38 (11): 1571-6, 2014.
  13. Cohen-Gogo S, Cellier C, Coindre JM, et al.: Ewing-like sarcomas with BCOR-CCNB3 fusion transcript: a clinical, radiological and pathological retrospective study from the Société Française des Cancers de L'Enfant. Pediatr Blood Cancer 61 (12): 2191-8, 2014.
  14. Postel-Vinay S, Véron AS, Tirode F, et al.: Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 44 (3): 323-7, 2012.
  15. Grünewald TG, Bernard V, Gilardi-Hebenstreit P, et al.: Chimeric EWSR1-FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite. Nat Genet 47 (9): 1073-8, 2015.

Langerhans Cell Histiocytosis

Studies published in 1994 showed clonality in Langerhans cell histiocytosis (LCH) using polymorphisms of methylation-specific restriction enzyme sites on the X-chromosome regions coding for the human androgen receptor, DXS255, PGK, and HPRT.[1,2] Biopsies of lesions with single-system or multisystem disease were found to have a proliferation of LCH cells from a single clone. The discovery of recurring genomic alterations (primarily BRAF V600E) in LCH (see below) confirmed the clonality of LCH in children. Pulmonary LCH in adults is usually nonclonal and it is possible that this group represents a reactive process to smoking.[3] However, a subset appeared to be clonal, as an analysis of BRAF mutations showed that a significant proportion of patients (25%–30%) have evidence for mutant BRAF V600E.[4]


BRAF-RAS pathway
Figure 8. Courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.

The genomic basis of LCH was advanced by a report in 2010 of an activating mutation of the BRAF oncogene (V600E) that was detected in 35 (57%) of 61 cases.[5] Multiple subsequent reports have confirmed the presence of BRAF V600E mutations in 50% or more of LCH cases in children.[6,7,8] Another BRAF mutation (BRAF 600DLAT) was identified, which resulted in the insertion of four amino acids and also appeared to activate signaling.[7]ARAF mutations are infrequent in LCH, but when present, can also lead to RAS-MAPK pathway activation.[9] No clinical characteristics associated with the BRAF V600E mutation have been identified.[5,6,7]

The RAS-MAPK signaling pathway (Figure 8) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E mutation of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[5,10]

Because RAS-MAPK pathway activation can be detected in all LCH cases, but not all cases have BRAF mutations, the presence of genomic alterations in other components of the pathway was suspected. Whole-exome sequencing of BRAF-mutated versus BRAF-wild type LCH biopsies revealed that 7 of 21 BRAF wild-type specimens had MAP2K1 mutations, while no BRAF–mutated specimens had MAP2K1 mutations.[10] The mutations in MAP2K1 (which codes for MEK) were activating, as indicated by their induction of ERK phosphorylation.[10] Another study showed MAP2K1 mutations exclusively in 11 of 22 BRAF wild-type cases.[11] Studies to date support the universal activation of ERK in LCH, with activation in most cases being explained by BRAF and MAP2K1 mutations.[5,10]

The presence of BRAF V600E mutation in blood and bone marrow was studied in a series of 100 patients, of which 65% tested positive for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique.[6] Circulating cells with the BRAF V600E mutation could be detected in all high-risk patients and in a subset of low-risk multisystem patients. The presence of circulating cells with the mutation conferred a twofold increased risk of relapse. The myeloid dendritic cell origin of LCH was confirmed by finding CD34+ stem cells with the mutation in the bone marrow of high-risk patients. Those with low-risk disease had more mature myeloid dendritic cells with the mutation, suggesting the stage of cell development is critical in defining the clinical characteristics of LCH, which can now be considered a myeloid neoplasia in most cases.

Clinical implications

Clinical implications of the described genomic findings include the following:

  • LCH joins a group of other pediatric entities with activating BRAF mutations, including select nonmalignant conditions (e.g., benign nevi) [12] and low-grade malignancies (e.g., pilocytic astrocytoma).[13,14] All of these conditions have a generally indolent course, with spontaneous resolution occurring in some cases. This distinctive clinical course may be a manifestation of oncogene-induced senescence.[12,15]
  • BRAF V600E mutations can be targeted by BRAF inhibitors (e.g., vemurafenib and dabrafenib) or by the combination of BRAF inhibitors plus MEK inhibitors (e.g., dabrafenib/trametinib and vemurafenib/cobimetinib). These agents and combinations are approved for adults with melanoma. Treatment of adults with combinations of a BRAF inhibitor and a MEK inhibitor showed significantly improved progression-free survival outcome compared with treatment using a BRAF inhibitor alone.[16,17] The most serious side effect of BRAF inhibitors is the induction of cutaneous squamous cell carcinomas,[16,17] with the incidence of these second cancers increasing with age;[18] reduction of this side effect can occur with concurrent treatment with both BRAF and MEK inhibitors.[16,17] Case reports have described activity of BRAF inhibitors against LCH in adult [19,20,21,22,23] and pediatric [24] patients, but there are insufficient data to assess the role of these agents in treatment of children with LCH.
  • With further research, the observation of BRAF V600E (or potentially mutated MAP2K1) in circulating cells may become a useful diagnostic tool to define high-risk versus low-risk disease.[6] Additionally, for patients who have a somatic mutation, persistence of circulating cells with the mutation may be useful as a marker of residual disease.[6]

(Refer to the PDQ summary on Langerhans Cell Histiocytosis Treatment for information about the treatment of childhood LCH.)

References:

  1. Willman CL, Busque L, Griffith BB, et al.: Langerhans'-cell histiocytosis (histiocytosis X)--a clonal proliferative disease. N Engl J Med 331 (3): 154-60, 1994.
  2. Yu RC, Chu C, Buluwela L, et al.: Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis. Lancet 343 (8900): 767-8, 1994.
  3. Dacic S, Trusky C, Bakker A, et al.: Genotypic analysis of pulmonary Langerhans cell histiocytosis. Hum Pathol 34 (12): 1345-9, 2003.
  4. Roden AC, Hu X, Kip S, et al.: BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases. Am J Surg Pathol 38 (4): 548-51, 2014.
  5. Badalian-Very G, Vergilio JA, Degar BA, et al.: Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 116 (11): 1919-23, 2010.
  6. Berres ML, Lim KP, Peters T, et al.: BRAF-V600E expression in precursor versus differentiated dendritic cells defines clinically distinct LCH risk groups. J Exp Med 211 (4): 669-83, 2014.
  7. Satoh T, Smith A, Sarde A, et al.: B-RAF mutant alleles associated with Langerhans cell histiocytosis, a granulomatous pediatric disease. PLoS One 7 (4): e33891, 2012.
  8. Sahm F, Capper D, Preusser M, et al.: BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis. Blood 120 (12): e28-34, 2012.
  9. Nelson DS, Quispel W, Badalian-Very G, et al.: Somatic activating ARAF mutations in Langerhans cell histiocytosis. Blood 123 (20): 3152-5, 2014.
  10. Chakraborty R, Hampton OA, Shen X, et al.: Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124 (19): 3007-15, 2014.
  11. Brown NA, Furtado LV, Betz BL, et al.: High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 124 (10): 1655-8, 2014.
  12. Michaloglou C, Vredeveld LC, Soengas MS, et al.: BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436 (7051): 720-4, 2005.
  13. Jones DT, Kocialkowski S, Liu L, et al.: Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 68 (21): 8673-7, 2008.
  14. Pfister S, Janzarik WG, Remke M, et al.: BRAF gene duplication constitutes a mechanism of MAPK pathway activation in low-grade astrocytomas. J Clin Invest 118 (5): 1739-49, 2008.
  15. Jacob K, Quang-Khuong DA, Jones DT, et al.: Genetic aberrations leading to MAPK pathway activation mediate oncogene-induced senescence in sporadic pilocytic astrocytomas. Clin Cancer Res 17 (14): 4650-60, 2011.
  16. Larkin J, Ascierto PA, Dréno B, et al.: Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N Engl J Med 371 (20): 1867-76, 2014.
  17. Long GV, Stroyakovskiy D, Gogas H, et al.: Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 386 (9992): 444-51, 2015.
  18. Anforth R, Menzies A, Byth K, et al.: Factors influencing the development of cutaneous squamous cell carcinoma in patients on BRAF inhibitor therapy. J Am Acad Dermatol 72 (5): 809-15.e1, 2015.
  19. Haroche J, Cohen-Aubart F, Emile JF, et al.: Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim-Chester disease. J Clin Oncol 33 (5): 411-8, 2015.
  20. Charles J, Beani JC, Fiandrino G, et al.: Major response to vemurafenib in patient with severe cutaneous Langerhans cell histiocytosis harboring BRAF V600E mutation. J Am Acad Dermatol 71 (3): e97-9, 2014.
  21. Gandolfi L, Adamo S, Pileri A, et al.: Multisystemic and Multiresistant Langerhans Cell Histiocytosis: A Case Treated With BRAF Inhibitor. J Natl Compr Canc Netw 13 (6): 715-8, 2015.
  22. Euskirchen P, Haroche J, Emile JF, et al.: Complete remission of critical neurohistiocytosis by vemurafenib. Neurol Neuroimmunol Neuroinflamm 2 (2): e78, 2015.
  23. Hyman DM, Puzanov I, Subbiah V, et al.: Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 373 (8): 726-36, 2015.
  24. Héritier S, Jehanne M, Leverger G, et al.: Vemurafenib Use in an Infant for High-Risk Langerhans Cell Histiocytosis. JAMA Oncol 1 (6): 836-8, 2015.

Retinoblastoma

Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.

Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4.[1,2] All children with bilateral disease and approximately 15% of patients with unilateral disease are presumed to have the heritable form, even though only 25% have an affected parent.

In heritable retinoblastoma, tumors tend to be diagnosed at a younger age than in the nonheritable form of the disease. Unilateral retinoblastoma in children younger than 1 year raises concern for heritable disease, whereas older children with a unilateral tumor are more likely to have the nonheritable form of the disease.[3]

The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[4,5] A rare cause of RB1 inactivation is chromothripsis, which may be difficult to detect by conventional methods.[6] Other recurring genomic changes that occur in a small minority of patients include BCOR mutation/deletion, MYCN amplification, and OTX2 amplification.[4,5,6] A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of RB1 loss. Approximately one-half of these cases with no evidence of RB1 loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed MCYN amplification.[5] A second report confirmed a case of retinoblastoma with wild-type RB1 and RB1 protein expression that showed MYCN amplification.[6]

(Refer to the PDQ summary on Retinoblastoma Treatment for information about the treatment of retinoblastoma.)

References:

  1. Castéra L, Sabbagh A, Dehainault C, et al.: MDM2 as a modifier gene in retinoblastoma. J Natl Cancer Inst 102 (23): 1805-8, 2010.
  2. de Oliveira Reis AH, de Carvalho IN, de Sousa Damasceno PB, et al.: Influence of MDM2 and MDM4 on development and survival in hereditary retinoblastoma. Pediatr Blood Cancer 59 (1): 39-43, 2012.
  3. Zajaczek S, Jakubowska A, Kurzawski G, et al.: Age at diagnosis to discriminate those patients for whom constitutional DNA sequencing is appropriate in sporadic unilateral retinoblastoma. Eur J Cancer 34 (12): 1919-21, 1998.
  4. Zhang J, Benavente CA, McEvoy J, et al.: A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481 (7381): 329-34, 2012.
  5. Rushlow DE, Mol BM, Kennett JY, et al.: Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14 (4): 327-34, 2013.
  6. McEvoy J, Nagahawatte P, Finkelstein D, et al.: RB1 gene inactivation by chromothripsis in human retinoblastoma. Oncotarget 5 (2): 438-50, 2014.

Kidney Tumors

Wilms Tumor

Wilms tumor can be viewed as a cancer of aberrant renal development. Mutations in many genes can perturb renal development and lead to cancer. This is in contrast to retinoblastoma, for example, in which a mutation in a single gene (RB1) is the oncogenic driver. Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or WTX.[1,2] Another subset of Wilms tumor cases result from mutations in miRNA processing genes (miRNAPG), including DROSHA, DGCR8, DICER1, and XPO5.[3,4,5,6] Other genes that are recurrently mutated in Wilms tumor include SIX1 and SIX2 (transcription factors that play key roles in early renal development) [3,4] and MLLT1 (a gene involved in transcriptional elongation in early development).[7] Anaplastic Wilms tumor is characterized by the presence of TP53 mutations.

Elevated rates of Wilms tumor are observed in a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome, Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[8] Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in REST and CTR9.[9,10]

The genomic and genetic characteristics of Wilms tumor are summarized below.

Wilms tumor 1gene (WT1)

The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[11]WT1 mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.[1,11,12] Wilms tumor with a WT1 mutation is characterized by the following:

  • Evidence of WNT pathway activation by activating mutations in the beta-catenin gene (CTNNB1) is common.[12,13,14]
  • Loss of heterozygosity at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal WT1 allele.[12,15]
  • Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests, which occur in approximately 20% of Wilms tumor cases, are observed at high rates in cases with genetic syndromes that have WT1 mutations such as WAGR and Denys-Drash syndrome.[16] Intralobar nephrogenic rests are also observed in cases with sporadic WT1 mutations.[17]
  • WT1 germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.[18,19]
  • WT1 mutations and 11p15 loss of heterozygosity were associated with relapse in patients with very low-risk Wilms tumor in one study of 56 patients who did not receive chemotherapy.[14] These findings need validation but may provide biomarkers for stratifying patients in the future.

Germline WT1 mutations are more common in children with Wilms tumor and one of the following:

  • WAGR syndrome, Denys-Drash syndrome,[20] or Frasier syndrome.[21]
  • Genitourinary anomalies, including hypospadias and cryptorchidism.
  • Bilateral Wilms tumor.
  • Unilateral Wilms tumor with nephrogenic rests in the contralateral kidney.
  • Stromal and rhabdomyomatous differentiation.

Syndromic conditions with germline WT1 mutations include WAGR syndrome, Denys-Drash syndrome,[20] and Frasier syndrome.[21] Each syndrome is described below.

  • WAGR syndrome. Children with WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) are at high risk (>30%) of developing Wilms tumor. WAGR syndrome results from deletions at chromosome 11p13 that involve a set of contiguous genes that includes the WT1 and PAX6 genes.

    Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Sporadic aniridia in which WT1 is not deleted is not associated with increased risk of Wilms tumor. Accordingly, children with familial aniridia, generally occurring for many generations, and without renal abnormalities, have a normal WT1 gene and are not at an increased risk of Wilms tumor.[22,23] Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests–associated favorable histology (FH) tumors of mixed cell type, and early age at diagnosis.[24] The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including SLC1A2 or BDNF (brain-derived neurotrophic factor).[25]

Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[26,27]

  • Denys-Drash and Frasier syndromes. Denys-Drash syndrome is characterized by nephrotic syndrome caused by diffuse mesangial sclerosis, XY pseudohermaphroditism, and increased risk of Wilms tumor. Frasier syndrome is characterized by progressive nephropathy caused by focal segmental glomerulosclerosis, gonadoblastoma, and XY pseudohermaphroditism.

    WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1.[20] By contrast, WT1 mutations in Frasier syndrome typically occur in intron 9 at the KTS site, and they affect an alternative splicing, thereby preventing production of the usually more abundant WT1 +KTS isoform.[28]

    Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[26,27] Bilateral Wilms tumor was more common in cases with WT1-truncating mutations (9 of 14 cases) compared with cases with WT1 missense mutations (3 of 27 cases).[26,27] These genomic studies confirm previous estimates of elevated risk of Wilms tumor for Denys-Drash syndrome and low risk of Wilms tumor for Frasier syndrome.

Children with WAGR syndrome or other germline WT1 mutations are monitored throughout their lives because they are at increased risk of developing hypertension, nephropathy, and renal failure.[29] Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.[30] Children with Wilms tumor and any genitourinary anomalies are also at increased risk of late renal failure and are monitored. Features associated with germline WT1 mutations that increase the risk of developing renal failure include the following:[29]

  • Stromal predominant histology.
  • Bilateral disease.
  • Intralobar nephrogenic rests.
  • Wilms tumor diagnosed before age 2 years.

Beta-cateningene (CTNNB1)

Somatic activating mutations of the CTNNB1 gene have been reported to occur in 15% of patients with Wilms tumor.[2,12,14,31] These CTNNB1 mutations result in activation of the WNT pathway, which plays a prominent role in the developing kidney.[32]CTNNB1 mutations commonly occur with WT1 mutations, and most Wilms tumors with WT1 mutations have a concurrent CTNNB1 mutation.[12,14,31] Activation of beta-catenin in the presence of intact WT1 protein appears to be inadequate to promote tumor development because CTNNB1 mutations are rarely found in the absence of a WT1 or WTX mutation.[2,33]CTNNB1 mutations appear to be late events in Wilms tumor development because they are found in tumors but not in nephrogenic rests.[17]

Wilms tumor gene on the X chromosome (WTX)

WTX, which is also called FAM123B, is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[34,1,2,12,35] Germline mutations in WTX cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373).[36] Despite having germline WTX mutations, individuals with osteopathia striata congenita are not predisposed to tumor development.[36] The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein.[33,37]WTX is most commonly altered by deletions involving part or all of the WTX gene, with deleterious point mutations occurring less commonly.[1,12,34] Most Wilms tumor cases with WTX alterations have epigenetic 11p15 abnormalities.[12]WTX alterations are equally distributed between males and females, and WTX inactivation has no apparent effect on clinical presentation or prognosis.[1]

Imprinting Cluster Regions (ICR) on chromosome 11p15 (WT2) and Beckwith-Wiedemann syndrome

A second Wilms tumor locus, WT2, maps to an imprinted region of chromosome 11p15.5; when it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms tumors have germline epigenetic or genetic changes at the 11p15.5 growth regulatory locus without any clinical manifestations of overgrowth. Like children with Beckwith-Wiedemann syndrome, these children have an increased incidence of bilateral Wilms tumor or familial Wilms tumor.[25]

Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[38] Various molecular mechanisms underlying Beckwith-Wiedemann syndrome have been identified. Some of these abnormalities are genetic (germline mutations of the maternal allele of CDKNIC, paternal uniparental isodisomy of 11 p15, or duplication of part of the 11p15 domain) but are more frequently epigenetic (loss of methylation of the maternal ICR2/KvDMR1 or gain of methylation of the maternal ICR1).[25,39]

Several candidate genes at the WT2 locus comprise the two independent imprinted domains IGF2/H19 and KIP2/LIT1.[39] Loss of heterozygosity, which exclusively affects the maternal chromosome, has the effect of upregulating paternally active genes and silencing maternally active ones. A loss or switch of the imprint for genes (change in methylation status) in this region has also been frequently observed and results in the same functional aberrations.[25,38,39]

A relationship between epigenotype and phenotype has been shown in Beckwith-Wiedemann syndrome, with a different rate of cancer in Beckwith-Wiedemann syndrome according to the type of alteration of the 11p15 region.[40] The overall tumor risk in patients with Beckwith-Wiedemann syndrome has been estimated to be between 5% and 10%, with a risk between 1% (loss of imprinting at ICR2) and 30% (gain of methylation at ICR1 and paternal 11p15 isodisomy). Development of Wilms tumor has been reported in patients with only ICR1 gain of methylation, whereas other tumors such as neuroblastoma or hepatoblastoma were reported in patients with paternal 11p15 isodisomy.[41,42,43]

Loss of imprinting or gene methylation is rarely found at other loci, supporting the specificity of loss of imprinting at 11p15.5.[44] Interestingly, Wilms tumors in Asian children are not associated with either nephrogenic rests or IGF2 loss of imprinting.[45]

Approximately one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[22,46,47] The prevalence of Beckwith-Wiedemann syndrome is about 1% among children with Wilms tumor reported to the National Wilms Tumor Study (NWTS).[47,48]

Other genes and chromosomal alterations

Additional genes have been implicated in the pathogenesis and biology of Wilms tumor, including the following:

  • miRNA-processing genes (miRNAPG). Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases.[3,4,5,6] The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 9).[49] The most commonly mutated miRNAPG is DROSHA, with a recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of DROSHA-mutated tumors. Other miRNAPG that are mutated in Wilms tumor include DGCR8, DICER1, TARBP2, DIS3L2, and XPO5. These mutations are generally mutually exclusive, and they appear to be deleterious and result in impaired expression of tumor-suppressing miRNAs. A striking sex bias was noted in mutations for DGCR8 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.[3,4]

    Germline mutations in miRNAPG are observed for DICER1 and DIS3L2, with mutations in the former causing DICER1 syndrome and mutations in the latter causing Perlman syndrome. DICER1 syndrome is typically caused by inherited truncating mutations in DICER1 with tumor formation following acquisition of a missense mutation in a domain of DICER1 (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs.[50] Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma.[50] Wilms tumor is an uncommon presentation of the DICER1 syndrome. Three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second DICER1 mutation in the RNase IIIb domain.[51] Another study identified DICER1 mutations in 2 of 48 familial Wilms tumor families.[52] Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with DICER1 mutations.[4,5]

    Perlman syndrome is a rare overgrowth disorder caused by mutations in DIS3L2, which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA.[53,54] The prognosis of Perlman syndrome is poor with a high neonatal mortality rate. In a survey of published cases of Perlman syndrome (N = 28), in infants who survived beyond the neonatal period, approximately two-thirds developed Wilms tumor and all showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.[55]


    Diagram showing the miRNA processing pathway, which is commonly mutated in Wilms' tumor.
    Figure 9. The miRNA processing pathway is commonly mutated in Wilms' tumor. Expression of mature miRNA is initiated by RNA polymerase–mediated transcription of DNA-encoded sequences into pri-miRNA, which form a long double-stranded hairpin. This structure is then cleaved by a complex of Drosha and DGCR8 (termed Pasha) into a smaller pre-miRNA hairpin, which is exported from the nucleus and then cleaved by Dicer (an RNase) and TRBP (with specificity for dsRNA) to remove the hairpin loop and leave two single-stranded miRNAs. The functional strand binds to Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides the complex to its target mRNA, while the nonfunctional strand is degraded. Targeting of mRNAs by this method results in mRNA silencing by mRNA cleavage, translational repression, or deadenylation. Let-7 miRNAs are a family of miRNAs highly expressed in ESCs with tumor suppressor properties. In cases in which LIN28 is overexpressed, LIN28 binds to pre-Let-7 miRNA, preventing DICER from binding and resulting in LIN28-activated polyuridylation by TUT4 or TUT7, causing reciprocal DIS3L2-mediated degradation of Let-7 pre-miRNAs. Genes involved in miRNA processing that have been associated with Wilms' tumor are highlighted in blue (inactivating) and green (activating) and include DROSHA, DGCR8, XPO5 (encoding exportin-5), DICER1, TARBP2, DIS3L2, and LIN28. Copyright © 2015 Hohenstein et al.; Published by Cold Spring Harbor Laboratory Press. Genes Dev. 2015 Mar 1; 29(5): 467–482. doi: 10.1101/gad.256396.114. This article is distributed exclusively by Cold Spring Harbor Laboratory Press under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

  • SIX1 and SIX2. SIX1 and SIX2 are highly homologous transcription factors that play key roles in early renal development and are expressed in the metanephric mesenchyme where they maintain the mesenchymal progenitor population. The frequency of SIX1 mutations is 3% to 4% in Wilms tumor and the frequency of SIX2 mutations in Wilms tumor is 1% to 3%.[3,4] Virtually all SIX1 and SIX2 mutations are in exon 1 and result in a glutamine-to-arginine mutation at position 177. Mutations in WT1, WTX, and CTNNB1 are infrequent in cases with SIX1/SIX2 or miRNAPG mutations. Conversely, SIX1/SIX2 mutations and miRNAPG mutations tended to occur together.
  • MLLT1. Approximately 4% of Wilms tumors have mutations in the highly conserved YEATS domain of MLLT1 (ENL), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development.[7] The mutant MLLT1 protein shows altered binding to acetylated histone tails. Patients with MLLT1-mutant tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating MLLT1 mutations early in renal development result in the development of Wilms tumor.
  • CTR9. Inactivating CTR9 germline mutations were identified in 3 of 35 familial Wilms tumor pedigrees.[10]CTR9, which is located at chromosome 11p15.3, is a key component of the polymerase-associated factor 1 complex (PAF1c) which has multiple roles in RNA polymerase II regulation and is implicated in embryonic organogenesis and maintenance of embryonic stem cell pluripotency.
  • TP53 (tumor suppressor gene). The majority of anaplastic Wilms tumors show mutations in the TP53 tumor suppressor gene.[56,57,58] It may be useful as an unfavorable prognostic marker.[56,57] A study of 40 patients with diffuse anaplastic Wilms tumor identified 25 patients with TP53 alterations (22 with TP53 mutations with or without 17p loss and three with only 17p loss). The 25 cases with TP53 alterations had a significantly lower event-free survival (EFS) and overall survival (OS) compared with those without TP53 alterations.[58] Microdissection of focally anaplastic Wilms tumors demonstrated TP53 mutations in anaplastic but not nonanaplastic areas of the tumor, suggesting that acquisition of TP53 mutation may be inherent in the process of becoming anaplastic.[59]
  • FBXW7. FBXW7, a ubiquitin ligase component, is a gene that has been identified as recurrently mutated at low rates in Wilms tumor. Mutations of this gene have been associated with epithelial-type tumor histology.[60]
  • 9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor.[61,62] The chromosomal region with germline deletion includes PTCH1, the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome). 9q22.3 microdeletion syndrome is characterized by the clinical findings of Gorlin syndrome, as well as developmental delay and/or intellectual disability, metopic craniosynostosis, obstructive hydrocephalus, prenatal and postnatal macrosomia, and seizures.[61] Five patients have been reported who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion.[62,63,64]
  • MYCN. MYCN copy number gain was observed in approximately 13% of Wilms tumor cases, and it was more common in anaplastic cases (7 of 23 cases, 30%) than in nonanaplastic cases (11.2%).[65] Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases.[65] Germline copy number gain at MYCN has been reported in a bilateral Wilms tumor case, and germline MYCN duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.[66]
  • REST. Inactivating germline mutations in REST (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees.[9] REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most REST mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. When 519 Wilms tumors were screened for REST mutations, 9 were found, and most were also present in the germline, sometimes with parents also positive for the mutation, strongly suggesting that it is a Wilms tumor predisposition gene, whether inherited from a parent or as a new mutation.[9] These observations indicate that REST is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.
  • 1q. Gain of 1q or overexpression of genes from 1q has been associated with an adverse outcome.

    In an analysis of FH Wilms tumors from 212 patients from NWTS-4 and the Pediatric Oncology Group Wilms Biology study, 27% of the tumors displayed 1q gain. A strong relationship between 1q gain and 1p/16q loss was observed. The 8-year EFS rate was 76% (95% confidence interval [CI], 63%–85%) for patients with 1q gain and 93% (95% CI, 87%–96%) for those lacking 1q gain (P = .0024). The 8-year OS rate was 89% (95% CI, 78%–94%) for those with 1q gain and 98% (95% CI, 94%–99%) for those lacking 1q gain (P = .0075). Gain of 1q was not found to correlate with disease stage. After stratification for stage of disease, 1q gain was associated with a significantly increased risk of disease recurrence (risk ratio estimate, 2.72; P = .0089).[67]

    Similar results have been reported by European investigators.[68]

  • 16q and 1p. Additional tumor-suppressor or tumor-progressive genes may lie on chromosomes 16q and 1p, as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumors, respectively.[69]
    • In large NWTS studies, patients with tumor-specific loss of these loci had significantly worse relapse-free survival and OS rates. Combined loss of 1p and 16q are used to select FH Wilms tumor patients for more aggressive therapy in the current Children's Oncology Group (COG) study. However, a U.K. study of more than 400 patients found no significant association between 1p deletion and poor prognosis, but a poor prognosis was associated with 16q loss of heterozygosity.[70]
    • An Italian study of 125 patients, using treatment quite similar to that in the COG study, found significantly worse prognosis in those with 1p deletions but not 16q deletions.[71]

    These conflicting results may arise from the greater prognostic significance of 1q gain described above. The loss of heterozygosity of 16q and 1p appear to arise from complex chromosomal events that result in 1q loss of heterozygosity or 1q gain. The change in 1q appears to be the critical tumorigenic genetic event.[67]

Figure 10 summarizes the genomic landscape of a selected cohort of Wilms tumors cases selected because they experienced relapse despite showing FH.[7] The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data resulting in six clusters. Five of six MLLT1-mutant tumors with available gene expression data were in cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with a mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both MLLT1 and with WT1/WTX/CTNNB1-mutated cases.


Chart showing unsupervised analysis of gene expression data for clinically distinctive favorable histology Wilms tumor.
Figure 10. Unsupervised analysis of gene expression data. Non-negative Matrix Factorization (NMF) analysis of 75 FHWT resulted in 6 clusters with the highest cophenetic correlation (0.95) after k=2. Five of six MLLT1 mutant tumours with available gene expression data occurred in NMF cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained four tumors with mutation or small segment deletion of WT1, all of which also had either a mutation of CTNNB1 or small segment deletion or mutation of WTX. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors). (Subsets 1 and 2 were low risk tumors and are therefore not represented in TARGET, Subsets 3 and 4 are highlighted in green and blue, respectively, and Subset 5 in white). Illustrated at the bottom are the expression patterns of genes of interest that were highly significantly differentially expressed between MLLT1-mutant and wild-type tumors. Copyright © 2015 Perlman, E. J. et al. MLLT1 YEATS domain mutations in clinically distinctive Favourable Histology wilms tumours. Nat. Commun. 6:10013 doi: 10.1038/ncomms10013 (2015). This article is distributed by Nature Publishing Group, a division of Macmillan Publishers Limited under a Creative Commons Attribution 4.0 International License, as described at http://creativecommons.org/licenses/by/4.0/.

Renal Cell Carcinoma

Translocation-positive carcinomas of the kidney are recognized as a distinct form of RCC and may be the most common form of renal cell carcinoma (RCC) in children. They are characterized by translocations involving the transcription factor E3 gene (TFE3) located on Xp11.2. The TFE3 gene may partner with one of the following genes:

  • ASPSCR in t(X;17)(p11.2;q25).
  • PRCC in t(X;1)(p11.2;q21).
  • SFPQ in t(X;1)(p11.2;p34).
  • NONO in inv(X;p11.2;q12).
  • Clathrin heavy chain (CLTC) in t(X;17)(p11;q23).

Another less-common translocation subtype, t(6;11)(p21;q12), involving an Alpha–transcription factor EB (TFEB) gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB induce overexpression of these proteins, which can be identified by immunohistochemistry.[72]

Previous exposure to chemotherapy is the only known risk factor for the development of Xp11 translocation RCCs. In one study, the postchemotherapy interval ranged from 4 to 13 years. All reported patients received either a DNA topoisomerase II inhibitor and/or an alkylating agent.[73,74]

Controversy exists as to the biological behavior of translocation RCC in children and young adults. Whereas some series have suggested a good prognosis when RCC is treated with surgery alone despite presenting at a higher stage (III/IV) than TFE-RCC, a meta-analysis reported that these patients have poorer outcomes.[75,76,77] The outcomes for these patients are being studied in the ongoing COG AREN03B2 (NCT00898365) biology and classification study. Vascular endothelial growth factor receptor–targeted therapies and mammalian target of rapamycin (mTOR) inhibitors seem to be active in Xp11 translocation metastatic RCC.[78] Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.[79]

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of renal cell carcinoma.)

Rhabdoid Tumors of the Kidney

Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1/INI1/SNF5/BAF47 gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[80,81] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by mutations that are commonly frameshift or nonsense mutations that lead to premature truncation of the SMARCB1 protein.[81,82] A small percentage of rhabdoid tumor cases are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[83,84] Exome sequencing of 35 cases of rhabdoid tumor identified a very low mutation rate, with no genes having recurring mutations other than SMARCB1, which appeared to contribute to tumorigenesis.[85]

Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[86,87] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 alterations.[81,88] In most cases, the mutations are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline mutation or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months).[89] Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis.[90,91] Germline mutations in SMARCA4 have also been reported in patients with rhabdoid tumors.[83,92]

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of rhabdoid tumor of the kidney.)

Clear Cell Sarcoma of the Kidney

Clear cell sarcoma of the kidney is an uncommon renal tumor that comprises approximately 5% of all primary renal malignancies in children, and is observed most often before age 3 years. The molecular background of clear cell sarcoma of the kidney is poorly understood due to its rarity and lack of experimental models.

Several biological features of clear cell sarcoma of the kidney have been described, including the following:

  • Internal tandem duplications in exon 15 of the BCOR gene (BCL6 corepressor) were reported in 100% (20 of 20 cases) of clear cell sarcoma of the kidney cases but in none of the other pediatric renal tumors evaluated.[93] Other reports have confirmed the finding of BCOR internal tandem duplications in clear cell sarcoma of the kidney.[94,95,96] Hence, BCOR internal tandem duplications appear to play a key role in the tumorigenesis of clear cell sarcoma of the kidney and their identification should aid in the differential diagnosis of renal tumors.[93]
  • The YWHAE-NUTM2 fusion (involving either NUTM2B or NUTM2E) resulting from t(10;17) was reported in 12% of cases of clear cell sarcoma of the kidney.[97] The presence of the YWHAE-NUTM2 fusion appears to be mutually exclusive with the presence of BCOR internal tandem duplications; this observation is based on a study of 22 cases of clear cell sarcoma of the kidney that included two cases with the YWHAE-NUTM2 fusion and 20 cases with BCOR internal tandem duplications.[94] The gene expression profiles for cases with the YWHAE-NUTM2 fusion were distinctive from those with BCOR internal tandem duplications.
  • Evaluation of 13 clear cell sarcoma of the kidney tumors for changes in chromosome copy number, mutations, and rearrangements found a single case with the YWHAE-NUTM2 fusion and twelve cases with BCOR internal tandem duplications.[96,98] No other recurrent segmental chromosomal copy number changes or somatic variants (single nucleotide or small insertion/deletion) were identified, providing further support for the role of BCOR internal tandem duplication as the primary oncogenic driver for clear cell sarcoma of the kidney.[98]

(Refer to the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for information about the treatment of clear cell tumor of the kidney.)

Melanoma

Melanoma-related conditions with malignant potential that arise in the pediatric population can be classified into three general groups:[99]

  • Large/giant congenital melanocytic nevus.
  • Spitzoid melanocytic tumors ranging from atypical Spitz tumors to spitzoid melanomas.
  • Melanoma arising in older adolescents that shares characteristics with adult melanoma (i.e., conventional melanoma).

The genomic characteristics of each tumor are summarized in Table 2.

The genomic landscape of conventional melanoma in children is represented by many of the genomic alterations found in adults with melanoma.[99] A report from the Pediatric Cancer Genome Project observed that 15 cases of conventional melanoma had a high burden of somatic single-nucleotide variations, TERT promoter mutations (12 of 13), and activating BRAF V600 mutations (13 of 15), as well as a mutational spectrum signature consistent with ultraviolet light damage. In addition, two-thirds of the cases had MC1R variants associated with an increased susceptibility to melanoma.

The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes including RET, ROS1, NTRK1, ALK, MET, and BRAF.[100,101,102] These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner.[99,101]TERT promoter mutations are uncommon in spitzoid melanocytic lesions and were observed in only 4 of 56 patients evaluated in one series. However, each of the four cases with TERT promoter mutations experienced hematogenous metastases.

Large congenital melanocytic nevi are reported to have activating NRAS Q61 mutations with no other recurring mutations noted.[103] Somatic mosaicism for NRAS Q61 mutations has also been reported in patients with multiple congenital melanocytic nevi and neuromelanosis.[104]

Table 2. Characteristics of Melanocytic Lesions
Tumor Affected Gene
Melanoma BRAF,NRAS,KIT, NF1
Spitzoid melanoma Kinase fusions (RET,ROS,MET,ALK,BRAF,NTRK1)
Spitz nevus HRAS;BRAFandNRAS(uncommon)
Acquired nevus BRAF
Dysplastic nevus BRAF,NRAS
Blue nevus GNAQ
Ocular melanoma GNAQ
Congenital nevi NRAS

(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood melanoma.)

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  52. Palculict TB, Ruteshouser EC, Fan Y, et al.: Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour. J Med Genet 53 (6): 385-8, 2016.
  53. Astuti D, Morris MR, Cooper WN, et al.: Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat Genet 44 (3): 277-84, 2012.
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  60. Williams RD, Al-Saadi R, Chagtai T, et al.: Subtype-specific FBXW7 mutation and MYCN copy number gain in Wilms' tumor. Clin Cancer Res 16 (7): 2036-45, 2010.
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  63. Garavelli L, Piemontese MR, Cavazza A, et al.: Multiple tumor types including leiomyoma and Wilms tumor in a patient with Gorlin syndrome due to 9q22.3 microdeletion encompassing the PTCH1 and FANC-C loci. Am J Med Genet A 161A (11): 2894-901, 2013.
  64. Cajaiba MM, Bale AE, Alvarez-Franco M, et al.: Rhabdomyosarcoma, Wilms tumor, and deletion of the patched gene in Gorlin syndrome. Nat Clin Pract Oncol 3 (10): 575-80, 2006.
  65. Williams RD, Chagtai T, Alcaide-German M, et al.: Multiple mechanisms of MYCN dysregulation in Wilms tumour. Oncotarget 6 (9): 7232-43, 2015.
  66. Fievet A, Belaud-Rotureau MA, Dugay F, et al.: Involvement of germline DDX1-MYCN duplication in inherited nephroblastoma. Eur J Med Genet 56 (12): 643-7, 2013.
  67. Gratias EJ, Jennings LJ, Anderson JR, et al.: Gain of 1q is associated with inferior event-free and overall survival in patients with favorable histology Wilms tumor: a report from the Children's Oncology Group. Cancer 119 (21): 3887-94, 2013.
  68. Segers H, van den Heuvel-Eibrink MM, Williams RD, et al.: Gain of 1q is a marker of poor prognosis in Wilms' tumors. Genes Chromosomes Cancer 52 (11): 1065-74, 2013.
  69. Grundy PE, Breslow NE, Li S, et al.: Loss of heterozygosity for chromosomes 1p and 16q is an adverse prognostic factor in favorable-histology Wilms tumor: a report from the National Wilms Tumor Study Group. J Clin Oncol 23 (29): 7312-21, 2005.
  70. Messahel B, Williams R, Ridolfi A, et al.: Allele loss at 16q defines poorer prognosis Wilms tumour irrespective of treatment approach in the UKW1-3 clinical trials: a Children's Cancer and Leukaemia Group (CCLG) Study. Eur J Cancer 45 (5): 819-26, 2009.
  71. Spreafico F, Gamba B, Mariani L, et al.: Loss of heterozygosity analysis at different chromosome regions in Wilms tumor confirms 1p allelic loss as a marker of worse prognosis: a study from the Italian Association of Pediatric Hematology and Oncology. J Urol 189 (1): 260-6, 2013.
  72. Argani P, Hicks J, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma (RCC): extended immunohistochemical profile emphasizing novel RCC markers. Am J Surg Pathol 34 (9): 1295-303, 2010.
  73. Argani P, Laé M, Ballard ET, et al.: Translocation carcinomas of the kidney after chemotherapy in childhood. J Clin Oncol 24 (10): 1529-34, 2006.
  74. Ramphal R, Pappo A, Zielenska M, et al.: Pediatric renal cell carcinoma: clinical, pathologic, and molecular abnormalities associated with the members of the mit transcription factor family. Am J Clin Pathol 126 (3): 349-64, 2006.
  75. Geller JI, Argani P, Adeniran A, et al.: Translocation renal cell carcinoma: lack of negative impact due to lymph node spread. Cancer 112 (7): 1607-16, 2008.
  76. Camparo P, Vasiliu V, Molinie V, et al.: Renal translocation carcinomas: clinicopathologic, immunohistochemical, and gene expression profiling analysis of 31 cases with a review of the literature. Am J Surg Pathol 32 (5): 656-70, 2008.
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  78. Malouf GG, Camparo P, Oudard S, et al.: Targeted agents in metastatic Xp11 translocation/TFE3 gene fusion renal cell carcinoma (RCC): a report from the Juvenile RCC Network. Ann Oncol 21 (9): 1834-8, 2010.
  79. Rais-Bahrami S, Drabick JJ, De Marzo AM, et al.: Xp11 translocation renal cell carcinoma: delayed but massive and lethal metastases of a chemotherapy-associated secondary malignancy. Urology 70 (1): 178.e3-6, 2007.
  80. Imbalzano AN, Jones SN: Snf5 tumor suppressor couples chromatin remodeling, checkpoint control, and chromosomal stability. Cancer Cell 7 (4): 294-5, 2005.
  81. Eaton KW, Tooke LS, Wainwright LM, et al.: Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 56 (1): 7-15, 2011.
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  94. Karlsson J, Valind A, Gisselsson D: BCOR internal tandem duplication and YWHAE-NUTM2B/E fusion are mutually exclusive events in clear cell sarcoma of the kidney. Genes Chromosomes Cancer 55 (2): 120-3, 2016.
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Thyroid Cancer

Studies have shown subtle differences between the genetic profiling of childhood differentiated thyroid carcinomas and that of adult tumors. A higher prevalence of RET/PTC rearrangements is seen in pediatric papillary carcinoma (45%–65% in children vs. 3%–34% in adults).[1]BRAF V600E mutations are seen in more than 50% of adults with papillary thyroid carcinoma;[2] although it likely occurs in a similar frequency in pediatric patients, studies have revealed a wide variation in frequency of this mutation.[1,2,3] In children, there does not appear to be a correlation between presence of the BRAF V600E mutation and stage or prognosis.[3] Differentiated thyroid carcinoma has been associated with germline DICER1 mutations and it is considered part of the DICER1 syndrome.[4]

Table 3. Comparison of Thyroid Carcinoma Characteristics in Children and Adolescents and Adultsa
Characteristic Children and Adolescents (%) Adults (%)
a Adapted from Yamashita et al.[5]
Histologic subtype:    
Papillary 67–98 85–90
Follicular 4–23 <10
Medullary 2–8 3
Poorly differentiated <0.1 2–7
 
Gene rearrangements:    
RET/PTC 38–87 0–35
NTRK 1 5–11 5–13
AKAP9-BRAF 11 1
PAX8-PPARG Unknown 0–50
 
Point mutations:    
BRAF 0–63 0–43
RASfamily 0–16 25–69
GNAS 0 11
TP53 0–23 0–20
 
Other:    
Multicentric 30–50 40–56
Lymph node involvement 30–90 5–55
Extrathyroid extension 24–51 16–46
Vascular invasion <31 14–37
Distant metastases 10–20 5–10

(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood thyroid cancer.)

References:

  1. Ballester LY, Sarabia SF, Sayeed H, et al.: Integrating Molecular Testing in the Diagnosis and Management of Children with Thyroid Lesions. Pediatr Dev Pathol 19 (2): 94-100, 2016 Mar-Apr.
  2. Rivkees SA, Mazzaferri EL, Verburg FA, et al.: The treatment of differentiated thyroid cancer in children: emphasis on surgical approach and radioactive iodine therapy. Endocr Rev 32 (6): 798-826, 2011.
  3. Henke LE, Perkins SM, Pfeifer JD, et al.: BRAF V600E mutational status in pediatric thyroid cancer. Pediatr Blood Cancer 61 (7): 1168-72, 2014.
  4. Slade I, Bacchelli C, Davies H, et al.: DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J Med Genet 48 (4): 273-8, 2011.
  5. Yamashita S, Saenko V: Mechanisms of Disease: molecular genetics of childhood thyroid cancers. Nat Clin Pract Endocrinol Metab 3 (5): 422-9, 2007.

Multiple Endocrine Neoplasia Syndromes

The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 4.

Table 4. Multiple Endocrine Neoplasia (MEN) Syndromes with Associated Clinical and Genetic Alterations
Syndrome Clinical Features/Tumors Genetic Alterations
MEN type 1: Werner syndrome[1] Parathyroid 11q13 (MEN1 gene)
Pancreatic islets: Gastrinoma 11q13 (MEN1 gene)
Insulinoma
Glucagonoma
VIPoma
Pituitary: Prolactinoma 11q13 (MEN1 gene)
Somatotrophinoma
Corticotropinoma
Other associated tumors (less common): Carcinoid: bronchial and thymic 11q13 (MEN1 gene)
Adrenocortical
Lipoma
Angiofibroma
Collagenoma
MEN type 2A: Sipple syndrome Medullary thyroid carcinoma 10q11.2 (RET gene)
Pheochromocytoma
Parathyroid gland
MEN type 2B Medullary thyroid carcinoma 10q11.2 (RET gene)
Pheochromocytoma
Mucosal neuromas
Intestinal ganglioneuromatosis
Marfanoid habitus
  • Multiple endocrine neoplasia type 1 (MEN1) syndrome (Werner syndrome): MEN1 syndrome is an autosomal dominant disorder characterized by the presence of tumors in the parathyroid, pancreatic islet cells, and anterior pituitary. Diagnosis of this syndrome should be considered when two endocrine tumors listed in Table 4 are present.

    A study documented the initial symptoms of MEN1 syndrome occurring before age 21 years in 160 patients.[2] Of note, most patients had familial MEN1 syndrome and were followed up using an international screening protocol.

    1. Primary hyperparathyroidism. Primary hyperparathyroidism, the most common symptom, was found in 75% of patients, usually only in those with biological abnormalities. Primary hyperparathyroidism diagnosed outside of a screening program is extremely rare, most often presents with nephrolithiasis, and should lead the clinician to suspect MEN1.[2,3]
    2. Pituitary adenomas. Pituitary adenomas were discovered in 34% of patients, occurred mainly in females older than 10 years, and were often symptomatic.[2]
    3. Pancreatic neuroendocrine tumors. Pancreatic neuroendocrine tumors were found in 23% of patients. Specific diagnoses included insulinoma, nonsecreting pancreatic tumor, and Zollinger-Ellison syndrome. The first case of insulinoma occurred before age 5 years.[2]
    4. Malignant tumors. Four patients had malignant tumors (two adrenal carcinomas, one gastrinoma, and one thymic carcinoma). The patient with thymic carcinoma died before age 21 years from rapidly progressive disease.

    Germline mutations of the MEN1 gene located on chromosome 11q13 are found in 70% to 90% of patients; however, this gene has also been shown to be frequently inactivated in sporadic tumors.[4] Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.[5]

    It is recommended that screening for patients with MEN1 syndrome begin by the age of 5 years and continue for life. The number of tests or biochemical screening is age specific and may include yearly serum calcium, parathyroid hormone, gastrin, glucagon, secretin, proinsulin, chromogranin A, prolactin, and IGF-1. Radiologic screening should include a magnetic resonance imaging of the brain and computed tomography of the abdomen every 1 to 3 years.[6]

  • Multiple endocrine neoplasia type 2A (MEN2A) and multiple endocrine neoplasia type 2B (MEN2B) syndromes:

    A germline activating mutation in the RET oncogene (a receptor tyrosine kinase) on chromosome 10q11.2 is responsible for the uncontrolled growth of cells in medullary thyroid carcinoma associated with MEN2A and MEN2B syndromes.[7,8,9]

    • MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 4) in an individual or in close relatives.[10]RET mutations in these patients are usually confined to exons 10 and 11.
    • MEN2B: MEN2B is characterized by medullary thyroid carcinomas, parathyroid hyperplasias, adenomas, pheochromocytomas, mucosal neuromas, and ganglioneuromas.[10,11,12] The medullary thyroid carcinomas that develop in these patients are extremely aggressive. More than 95% of mutations in these patients are confined to codon 918 in exon 16, causing receptor autophosphorylation and activation.[13] Patients also have medullated corneal nerve fibers, distinctive faces with enlarged lips, and an asthenic Marfanoid body habitus.

      A pentagastrin stimulation test can be used to detect the presence of medullary thyroid carcinoma in these patients, although management of patients is driven primarily by the results of genetic analysis for RET mutations.[13,14]

    Guidelines for genetic testing of suspected patients with MEN2 syndrome and the correlations between the type of mutation and the risk levels of aggressiveness of medullary thyroid cancer have been published.[14,15]

  • Familial Medullary Thyroid Carcinoma: Familial medullary thyroid carcinoma is diagnosed in families with medullary thyroid carcinoma in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia. RET mutations in exons 10, 11, 13, and 14 account for most cases.

    The most-recent literature suggests that this entity should not be identified as a form of hereditary medullary thyroid carcinoma that is separate from MEN2A and MEN2B. Familial medullary thyroid carcinoma should be recognized as a variant of MEN2A, to include families with only medullary thyroid cancer who meet the original criteria for familial disease. The original criteria includes families of at least two generations with at least two, but less than ten, patients with RET germline mutations; small families in which two or fewer members in a single generation have germline RET mutations; and single individuals with a RET germline mutation.[14,16]

Table 5. Clinical Features of Multiple Endocrine Neoplasia Type 2 (MEN2) Syndromes
MEN2 Subtype Medullary Thyroid Carcinoma Pheochromocytoma Parathyroid Disease
MEN2A 95% 50% 20% to 30%
MEN2B 100% 50% Uncommon

(Refer to the PDQ summary on Unusual Cancers of Childhood Treatment for information about the treatment of childhood MEN syndromes.)

References:

  1. Thakker RV: Multiple endocrine neoplasia--syndromes of the twentieth century. J Clin Endocrinol Metab 83 (8): 2617-20, 1998.
  2. Goudet P, Dalac A, Le Bras M, et al.: MEN1 disease occurring before 21 years old: a 160-patient cohort study from the Groupe d'étude des Tumeurs Endocrines. J Clin Endocrinol Metab 100 (4): 1568-77, 2015.
  3. Romero Arenas MA, Morris LF, Rich TA, et al.: Preoperative multiple endocrine neoplasia type 1 diagnosis improves the surgical outcomes of pediatric patients with primary hyperparathyroidism. J Pediatr Surg 49 (4): 546-50, 2014.
  4. Farnebo F, Teh BT, Kytölä S, et al.: Alterations of the MEN1 gene in sporadic parathyroid tumors. J Clin Endocrinol Metab 83 (8): 2627-30, 1998.
  5. Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007.
  6. Thakker RV: Multiple endocrine neoplasia type 1 (MEN1). Best Pract Res Clin Endocrinol Metab 24 (3): 355-70, 2010.
  7. Sanso GE, Domene HM, Garcia R, et al.: Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers. Cancer 94 (2): 323-30, 2002.
  8. Alsanea O, Clark OH: Familial thyroid cancer. Curr Opin Oncol 13 (1): 44-51, 2001.
  9. Fitze G: Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg 14 (6): 375-83, 2004.
  10. Puñales MK, da Rocha AP, Meotti C, et al.: Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A. Thyroid 18 (12): 1261-8, 2008.
  11. Skinner MA, DeBenedetti MK, Moley JF, et al.: Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B. J Pediatr Surg 31 (1): 177-81; discussion 181-2, 1996.
  12. Brauckhoff M, Gimm O, Weiss CL, et al.: Multiple endocrine neoplasia 2B syndrome due to codon 918 mutation: clinical manifestation and course in early and late onset disease. World J Surg 28 (12): 1305-11, 2004.
  13. Sakorafas GH, Friess H, Peros G: The genetic basis of hereditary medullary thyroid cancer: clinical implications for the surgeon, with a particular emphasis on the role of prophylactic thyroidectomy. Endocr Relat Cancer 15 (4): 871-84, 2008.
  14. Waguespack SG, Rich TA, Perrier ND, et al.: Management of medullary thyroid carcinoma and MEN2 syndromes in childhood. Nat Rev Endocrinol 7 (10): 596-607, 2011.
  15. Kloos RT, Eng C, Evans DB, et al.: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 19 (6): 565-612, 2009.
  16. Wells SA Jr, Asa SL, Dralle H, et al.: Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid 25 (6): 567-610, 2015.

Changes to this Summary (08 / 05 / 2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

This is a new summary.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genomics of childhood cancer. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

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