National Cancer Institute

Expert-reviewed information summary about the genomics of childhood cancer. The summary describes the molecular subtypes for specific pediatric cancers and their associated clinical characteristics, the recurring genomic alterations that characterize each subtype at diagnosis or relapse, and the therapeutic and prognostic significance of the genomic alterations. The genomic alterations associated with brain tumors, kidney tumors, leukemias, lymphomas, sarcomas, and other cancers are discussed.

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the genomics of childhood cancer. The summary describes the molecular subtypes for specific pediatric cancers and their associated clinical characteristics, the recurring genomic alterations that characterize each subtype at diagnosis or relapse, and the therapeutic and prognostic significance of the genomic alterations. The genomic alterations associated with brain tumors, kidney tumors, leukemias, lymphomas, sarcomas, and other cancers are discussed. This summary 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.

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).

Childhood Cancer Genomics

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:

  • fusion genes associated with anaplastic large cell lymphoma cases.
  • point mutations associated with a subset of neuroblastoma cases.
  • and other kinase genomic alterations associated with subsets of pediatric glioma cases.
  • Hedgehog pathway mutations associated with a subset of medulloblastoma cases.
  • 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 mutations almost exclusively among pediatric midline high-grade gliomas.
  • The loss of in rhabdoid tumors.
  • The presence of 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 ) and medulloblastoma (structural variants juxtapose or coding sequences proximal to active enhancer elements leading to transcriptional activation []). 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. In some cases, the pathogenic germline mutations are clearly contributory to the patient’s cancer (e.g., 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 and that have an undefined role in childhood cancer predisposition). The frequency of germline mutations varies by tumor type (e.g., lower for neuroblastoma and higher for osteosarcoma), and many of the identified germline mutations fit into known predisposition syndromes (e.g., for pleuropulmonary blastoma, and for rhabdoid tumor and small cell ovarian cancer, for adrenocortical carcinoma and Li-Fraumeni syndrome cancers, 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.


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. Figure 1 illustrates the distribution of ALL cases by cytogenetic/molecular subtype.

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. Reprinted from Seminars in Hematology, Volume 50, Charles G. Mullighan, Genomic Characterization of Childhood Acute Lymphoblastic Leukemia, Pages 314–324, Copyright (2013), with permission from Elsevier.

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 family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., and ), point mutations (e.g., and ), and intragenic/intergenic deletions (e.g., , , , and ).

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., and , and ()-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within distinctive biological subtypes:

  • deletions and mutations are most commonly observed within cases of Philadelphia chromosome–positive (Ph+) ALL and Ph-like ALL.
  • Intragenic deletions occur within a distinctive subtype characterized by this alteration and lacking other recurring cytogenetic alterations associated with pediatric B-precursor ALL.
  • mutations occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes, and the mutations in these patients are often germline. 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 genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with Ph-like ALL that have abnormalities, although mutations are also observed in approximately 15% of children with Down syndrome ALL. 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. mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and ()-rearranged ALL, and are rare in other subtypes.

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. Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in are not found at diagnosis whereas specific mutations in 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. mutations are uncommon in patients with late relapse, and they appear to induce resistance to 6-mercaptopurine and thioguanine. Another gene that is found mutated only at relapse is , a gene involved purine biosynthesis. 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 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids. 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 precursor B-cell ALL. Some chromosomal alterations are associated with more favorable outcomes, such as high hyperdiploidy (51–65 chromosomes) and the fusion. Others historically have been associated with a poorer prognosis, including the Philadelphia chromosome (t(9;22)(q34;q11.2)), rearrangements of the () gene, hypodiploidy, and intrachromosomal amplification of the gene (iAMP21).

In recognition of the clinical significance of many of these genomic alterations, the 2016 revision of the World Health Organization classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for precursor B-cell ALL:

  • B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
  • B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
  • B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); .
  • B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); rearranged.
  • B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); .
  • B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
  • B-lymphoblastic leukemia/lymphoma with hypodiploidy.
  • B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); .
  • B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma, .
  • Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

These and other chromosomal and genomic abnormalities for childhood ALL are described below.

(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., , , and ) and mutations (e.g., and ) account for many of the remaining cases.

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. 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., and mutations being much more common in adults than children). Figure 3 (B) shows that common genomic alterations in adult AML (, , and 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. Reprinted from Pediatric Clinics of North America, Volume 62, Katherine Tarlock, Soheil Meshinchi, Pediatric Acute Myeloid Leukemia: Biology and Therapeutic Implications of Genomic Variants, Pages 75–93, Copyright (2015), with permission from Elsevier.

Figure 4 (A) shows the marked variation in ()-rearranged AML by age, with much higher frequencies for infants compared with older children and adults. 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 (, , and ) and vary by age.

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. Reprinted from Pediatric Clinics of North America, Volume 62, Katherine Tarlock, Soheil Meshinchi, Pediatric Acute Myeloid Leukemia: Biology and Therapeutic Implications of Genomic Variants, Pages 75–93, Copyright (2015), with permission from Elsevier.

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. 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 ( < .001). This observation is consistent with previous results showing that presence of the mutation predicted for poor prognosis only when there was a high 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. 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. 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 , , , , and . 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), , and ). () 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

Molecular abnormalities associated with favorable prognosis include the following:

    • t(8;21) (): In leukemias with t(8;21), the ) gene on chromosome 21 is fused with the () gene on chromosome 8. The t(8;21) translocation is associated with the FAB M2 subtype and with granulocytic sarcomas. Adults with t(8;21) have a more favorable prognosis than adults with other types of AML. These children have a more favorable outcome compared with children with AML characterized by normal or complex karyotypes with 5-year overall survival (OS) of 80% to 90%. The t(8;21) translocation occurs in approximately 12% of children with AML.

      Although both and fusion genes disrupt the activity of core-binding factor, which contains RUNX1 and CBFB, cases with these genomic alterations have distinctive secondary mutations. Both subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., , and ); and are the most commonly mutated genes for both subtypes. cases additionally have frequent mutations in genes regulating chromatin conformation (e.g., and ) and genes encoding members of the cohesin complex (approximately 40% and 20% of cases, respectively). Mutations in and and mutations in members of the cohesin complex are rare in leukemias. Data exist (primarily from adults) that these secondary mutations may have prognostic significance, but further study is required to understand their prognostic significance in children. Additionally, mutations may indicate increased risk of treatment failure for patients with core-binding factor AML, although the prognostic significance of mutations may be dependent on the mutant-allele ratio (high ratio unfavorable) and/or the specific type of mutation (exon 17 mutations unfavorable). exon 17 mutations are enriched in patients with fusions when compared with patients with fusions.

    • inv(16) (): In leukemias with inv(16), the gene () at chromosome band 16q22 is fused with the gene at chromosome band 16p13. The inv(16) translocation is associated with the FAB M4Eo subtype. Inv(16) confers a favorable prognosis for both adults and children with AML with a 5-year OS of about 85%. Inv(16) occurs in 7% to 9% of children with AML. As noted above, cases with and cases with have distinctive secondary mutations; secondary mutations are primarily restricted to genes that activate receptor tyrosine kinase signaling (, , and ).
  • t(15;17) (): 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- retinoic acid. The t(15;17) translocation leads to the production of a fusion protein involving the retinoid acid receptor alpha and PML. 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 gene).
  • Nucleophosmin () 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 mutations by the demonstration of cytoplasmic localization of . 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, and an improved prognosis in the absence of -internal tandem duplication () mutations in adults and younger adults.

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

  • mutations: Mutations in the gene () 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 . Outcome for adults with AML with mutations appears to be relatively favorable and similar to that of patients with core-binding factor leukemias. Studies in adults with AML have demonstrated that double-mutant, but not single-allele mutant, AML was independently associated with a favorable prognosis.

    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. Although both double- and single-mutant alleles of were associated with a favorable prognosis in children with AML in one large study, a second study observed inferior outcome for patients with single mutations. However, very low numbers of children with single-allele mutants were included in these two studies (only 13 ), making a conclusion regarding the prognostic significance of single-allele mutations in children premature. In newly diagnosed patients with double-mutant AML, in addition to usual family history queries, germline screening should be considered because 5% to 10% of these patients are reported to have a germline mutation.

Molecular abnormalities associated with an unfavorable prognosis

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). These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.

    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. However, outcome for children with del(7q), but not monosomy 7, appears to be comparable to that of other children with AML. The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).

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

  • Chromosome 3 (inv(3)(q21;q26) or t(3;3)(q21;q26)) and overexpression: The inv(3) and t(3;3) abnormalities involving the gene located at chromosome 3q26 are associated with poor prognosis in adults with AML, but are very uncommon in children (<1% of pediatric AML cases).
  • mutations: Presence of a - mutation appears to be associated with poor prognosis in adults with AML, particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele. - mutations also convey a poor prognosis in children with AML. The frequency of - 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). The prevalence of - is increased in certain genomic subtypes of pediatric AML, including those with the fusion gene, of which 80% to 90% have -. Approximately 15% of patients with - have -, and patients with both - and - have a poorer prognosis than do patients with - and without -.

    For APL, - and point mutations occur in 30% to 40% of children and adults. Presence of the - mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis. It remains unclear whether mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all- retinoic acid and arsenic trioxide.

    Activating point mutations of 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

Other molecular abnormalities observed in pediatric AML include the following:

  • () gene rearrangements: Translocations of chromosomal band 11q23 involving the gene, including most AMLs secondary to epipodophyllotoxin, are associated with monocytic differentiation (FAB M4 and M5). rearrangements are also reported in 5% to 10% of FAB M7 (AMKL) patients.

    The most common translocation, representing approximately 50% of -rearranged cases in the pediatric AML population, is t(9;11)(p22;q23) in which the gene is fused with the gene. An gene rearrangement occurs in approximately 20% of children with AML. However, more than 50 different fusion partners have been identified for the gene in patients with AML. The median age for 11q23/-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. 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).

    Outcome for patients with de novo AML and () gene rearrangement is generally reported as being similar to that for other patients with AML. However, as the 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 -rearranged AML. For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/-rearranged AML, showed a highly favorable outcome with 5-year event-free survival (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 gene is fused with the gene, the international retrospective study did not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. 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.

    Several 11q23/ ()-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. Some cases with the t(10;11) translocation have fusion of the gene with the - at 10p12, while others have fusion of with at 10p11.2. 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. 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. A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.

  • t(6;9) (): t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214. This subgroup of AML has been associated with a poor prognosis in adults with AML, 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 -. 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.
    • : is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)) that is present in approximately 2% of pediatric AML. It occurs most frequently in non–Down syndrome AMKL (~15% of patients), but also has been observed in other cytogenetically normal pediatric AML subtypes (~4% of patients). It has been associated with an inferior outcome.
    • (also called ): is a recurrent cryptic translocation in pediatric AMKL, accounting for 9% to 10% of AMKL cases and having a median age at presentation of approximately 2 years. This lesion appears to confer a high risk of relapse (36% ± 14%) and poor EFS and OS (36% ± 13% for each).
    • t(1;22) (): The t(1;22)(p13;q13) translocation is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL). Studies have found that t(1;22)(p13;q13) is observed in 12% to 14% of children with AMKL and evaluable cytogenetics or molecular genetics. 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. The translocation is uncommon in children with Down syndrome who develop AMKL. In leukemias with t(1;22), the () gene on chromosome 1 is fused to the () gene on chromosome 22. Cases with detectable fusion transcripts in the absence of t(1;22) have also been reported.

      Controversy exists regarding the prognostic significance of the t(1;22) in pediatric AMKL. In a report from the Berlin-Frankfurt-Münster (BFM) study group of 97 non–Down syndrome AMKL patients, presence of t(1;22) (n = 8) was associated with a significantly inferior outcome (5-year EFS, 38% vs. 53% in other AMKL patients), although all of the observed events in patients with t(1;22) were related to treatment-related mortality. An international collaborative retrospective study with a larger number of t(1;22) cases reported that patients with this abnormality had a 5-year EFS of 54.5% and an OS of 58.2%, similar to the rates for other children with AMKL. In another international retrospective analysis of 153 cases with non–Down syndrome AMKL with samples available for molecular analysis, the 4-year EFS for patients with t(1;22) was 59% and OS was 70%, significantly better than AMKL patients with other specific genetic abnormalities (, , rearrangements, monosomy7).

  • t(8;16) (): The t(8;16) translocation fuses the gene on chromosome 8p11 to 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. 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. These observations suggest that a policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.
  • t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of (). The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH. This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with () rearrangement, and is associated with a high risk of treatment failure.
  • gene fusions: has been reported to form leukemogenic gene fusions with more than 20 different partners. In the pediatric AML setting, the two most common fusion genes are and , 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. AML cases with either fusion gene show high expression of and genes, indicative of a stem cell phenotype.

    The fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35). This alteration occurs in approximately 4% to 5% of pediatric AML cases. 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). - cases present with high WBC count (median, 147 × 10/L in one study). Most AML cases do not show cytogenetic aberrations. A high percentage of cases (80% to 90%) have . A study that included 12 children with - AML reported that although all patients achieved CR, presence of independently predicted for poor prognosis, and children with AML had a high risk of relapse, with a resulting 4-year EFS of approximately 10%. In another study that included children (n = 38) and adults (n = 7) with - AML, presence of both - and - 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%).

  • mutations: Although mutations in have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown. Mutations in are observed more commonly than mutations in pediatric AML cases. mutations occur with similar frequency for all Type II alteration subtypes with the exception of APL, for which mutations are seldom observed.
  • mutations: Mutations in occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities. The presence of activating mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without mutation. The prognostic significance of mutations occurring in pediatric core-binding factor AML remains unclear, although the largest pediatric study reported to date observed no prognostic significance for mutations.
  • mutations: mutations are present in most, if not all, Down syndrome children with either transient myeloproliferative disease or AMKL. mutations are not observed in non–Down syndrome children with AMKL or in Down syndrome children with other types of leukemia. is a transcription factor that is required for normal development of erythroid cells, megakaryocytes, eosinophils, and mast cells. 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.
  • mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults. The mutation has been shown in some, but not all, studies to be an independent predictor of worse disease-free, event-free, and OS of adults. In children with AML, mutations are observed in approximately 10% of cases. Cases with mutations are enriched among children with normal cytogenetics and -, but are less common among children younger than 3 years. AML cases with are enriched for both - and mutations. In univariate analyses, mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of mutation status is unclear because of its strong association with - and its association with . The largest study of mutations in children with AML observed that children with mutations in the absence of - had outcomes similar to that of children without mutations, while children with both mutation and - had survival rates less than 20%.
  • mutations: Mutations of the gene () 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. Mutations in this gene are independently associated with poor outcome. mutations appear to be very uncommon in children.
  • and mutations: Mutations in and , which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML, and they are enriched in patients with mutations. The specific mutations that occur in and create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate. This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in . Mutations in and are uncommon in pediatric AML, occurring in 0% to 4% of cases. There is no indication of a negative prognostic effect for and mutations in children with AML.
  • mutations: is the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor, and activating mutations in are observed in 2% to 3% of pediatric AML cases. These mutations lead to enhanced signaling through the G-CSF receptor, and they are primarily observed in AML with either mutations or with core-binding factor abnormalities ( and inversion 16). The clinical characteristics of and prognosis for patients with mutations do not seem to be significantly different from those of patients without mutations.

    Activating mutations in are also observed in patients with severe congenital neutropenia. These mutations are not the cause of severe congenital neutropenia, but rather arise as somatic mutations and can represent an early step in the pathway to AML. In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had mutations detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed mutations. A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed mutations in approximately 80%, and also observed a high frequency of mutations (approximately 60%), suggesting cooperation between and mutations for leukemia development within the context of severe congenital neutropenia.

  • miR-155 expression: miR-155 is a microRNA that is normally upregulated in hematopoietic cells and myeloid progenitor cells as part of an inflammatory response but when aberrantly dysregulated and highly expressed, it independently enhances survival and growth factor independence through repression of PU.1. A study of 363 adults with cytogenetically normal AML found that miR-155 was highly associated with induction failure, disease-free survival, and OS. An independent study of children with cytogenetically normal AML (N = 198) similarly found miR-155 to be an adverse factor. Induction failure (54% vs. 17%; < .001), 3-year OS (51% vs. 75%; = .002), and EFS (32% vs. 59%; < .001) were all worse in patients with high miR-155 expression. As with adults, children in this trial who had high miR-155 expression were more likely to have mutations (69%; < .001). Multivariate analyses found that miR-155 maintained an independent adverse impact on these outcome parameters when controlling for age; white blood cell count; and , , and mutations.

(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: , , , , and . In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 5). Patients with mutated accounted for 19% of cases, and patients with mutated accounted for 15% of cases. and 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, a finding that is associated with poorer prognosis.

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. Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., 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., was mutated in 7%–9% of cases). mutations are also observed in a small percentage (4%–12%) of JMML cases. Cases with germline and germline mutations showed low rates of additional mutations (refer to Figure 5).

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. 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. 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 mutation. Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.
  • 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, and there are no clinical data available.

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).

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 oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of , a gene involved in cellular proliferation. The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.

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.

Cytogenetic evidence of 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. BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.

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

(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).

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 gene product and CD10. The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.
  • Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the gene that is seen in adults.
  • 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.
  • 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 rearrangement and with approximately one-half of the nonrearranged cases showing gain or amplification.
  • A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an 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.

(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. 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.
  • 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 and , respectively) and commonly shows inactivation of by either mutation or gene deletion. 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.

(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.

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 mutations were seen in 60% of patients, but mutations are rarely seen in patients with loss of heterozygosity in 6q16.

(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.

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 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 translocations. Anti-ALK immunohistochemical staining pattern is quite specific for the type of translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant translocations.

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

In a European series of 375 children and adolescents with systemic -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; = .002). The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the (NCT00059839) study, despite a different chemotherapy backbone.

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

Central Nervous System Tumors

Central nervous system (CNS) tumors include pilocytic astrocytomas and other astrocytic tumors, diffuse astrocytic tumors, brain stem gliomas, CNS atypical teratoid/rhabdoid tumors, medulloblastomas, nonmedulloblastoma embryonal tumors, and ependymomas.

The terminology of the 2016 World Health Organization (WHO) Classification of Tumors of the Central Nervous System is used below. The 2016 WHO CNS classification incorporates genomic features in addition to histology, and it includes multiple changes from the previous 2007 WHO classification. Of particular relevance for childhood brain cancers is the new entity , which includes diffuse intrinsic pontine glioma (DIPG) with the mutation and other high-grade gliomas of the midline with the mutation. Other examples of molecularly defined entities discussed below are -fusion–positive ependymoma, WNT-activated and SHH-activated medulloblastoma, and embryonal tumor with multilayered rosettes, -altered.

Pilocytic Astrocytomas and Other Astrocytic Tumors

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

activation in pilocytic astrocytoma occurs most commonly through a - gene fusion, producing a fusion protein that lacks the BRAF regulatory domain. This fusion is seen in most infratentorial and midline pilocytic astrocytomas, but is present at lower frequency in supratentorial (hemispheric) tumors.

Presence of the 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. However, other factors such as deletion, whole chromosome 7 gain, and tumor location may modify the impact of the mutation on outcome.; [] Progression to high-grade glioma is rare for pediatric low-grade glioma with the fusion.

activation through the fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).

Other genomic alterations in pilocytic astrocytomas that can activate the ERK/MAPK pathway (e.g., alternative gene fusions, rearrangements, mutations, and V600E point mutations) are less commonly observed. V600E point mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma, desmoplastic infantile ganglioglioma, and approximately two-thirds of pleomorphic xanthoastrocytomas. One retrospective study of 53 children with gangliogliomas demonstrated 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%). Similarly, children with diencephalic low-grade astrocytomas with a V600E mutation had a 5-year PFS of 22%, compared with a 52% PFS in children who were wildtype.[] The frequency of the 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).

Angiocentric gliomas have been noted to largely harbor - fusions, a putative driver mutation for this relatively rare class of gliomas.

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

Activating mutations in , , and in fusion genes have also been identified in noncerebellar pilocytic astrocytomas. 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.

Most children with tuberous sclerosis have a mutation in one of two tuberous sclerosis genes (/hamartin or /tuberin). Either of these mutations results in activation 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. Because subependymal giant cell astrocytomas are driven by mTOR activation, mTOR inhibitors are active agents that can induce tumor regression in children with these tumors.

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

Diffuse Astrocytic Tumors

This category includes, among other diagnoses, diffuse astrocytomas (grade II) and pediatric high-grade gliomas (anaplastic astrocytoma [grade III], glioblastoma [grade IV], and diffuse midline glioma, -mutant (grade IV]).

Diffuse astrocytomas

For pediatric diffuse astrocytomas (grade II), rearrangements in the MYB family of transcription factors ( and ) are the most commonly reported genomic alteration. Other alterations observed include alterations (primarily duplications involving the tyrosine kinase domain), alterations, mutations, and family mutations. mutations, which are the most common genomic alteration in adult diffuse astrocytomas, are uncommon in children with diffuse astrocytomas and, when present, are observed almost exclusively in older adolescents.

Anaplastic astrocytomas and glioblastomas

Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.

  • Pediatric high-grade gliomas have and genomic alterations less frequently and genomic alterations and mutations in histone genes (primarily histone 3.3 [] but also histone 3.1 []) more frequently than do adult tumors.
  • Although it was believed that pediatric glioblastoma multiforme tumors were more closely related to adult glioblastoma multiforme tumors in which there is stepwise transformation from lower-grade into higher-grade gliomas and in which most tumors have and mutations, the latter mutations are rarely observed in children younger than 15 years with high-grade gliomas. mutations are observed in older adolescents with high-grade gliomas.

Pediatric glioblastoma multiforme tumors are separated into relatively distinct subgroups on the basis of epigenetic patterns (DNA methylation), with distinctive chromosome copy number gains/losses and gene mutations. Two subgroups have identifiable recurrent mutations in (the gene encoding histone 3.3), suggesting disrupted epigenetic regulatory mechanisms, with the most recognized subgroup having mutations at K27 (lysine 27) and the other group having mutations at G34 (glycine 34). The subgroups are the following:

  • mutation at K27: The K27 cluster occurs predominately in mid-childhood (median age, approximately 10 years), is mainly midline (thalamus, brain stem, and spinal cord), and carries a very poor prognosis. These tumors also frequently have mutations. Thalamic high-grade gliomas in older adolescents and young adults also show a high rate of K27 mutations. The 2016 WHO classification groups these cancers into a single entity, diffuse midline glioma, -mutant.
  • mutation at G34: The second mutation tumor cluster, the G34 grouping, is found in somewhat older children and young adults (median age, 14–18 years), arises exclusively in the cerebral cortex, and carries a somewhat better prognosis. The G34 clusters also have mutations and widespread hypomethylation across the whole genome. Patients with mutations are at high risk of treatment failure, but the prognosis is not as poor as it is for patients with mutations.

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

Pediatric glioblastoma multiforme patients whose tumors have mutations are almost exclusively older adolescents (median age in a pediatric population, 16 years) with hemispheric tumors. -mutated cases often show mutations, promoter methylation, and a glioma-CpG island methylator phenotype (G-CIMP). Pediatric patients with mutations show a more favorable prognosis than do other pediatric glioblastoma multiforme patients.

A fourth group of pediatric glioblastoma multiforme patients identified by DNA methylation analysis are those lacking both histone mutations and mutations. This is a heterogeneous group with higher rates of gene amplifications than other pediatric glioblastoma multiforme subtypes. The most commonly amplified genes are , , , and .

DNA methylation analysis of tumor tissue may identify pediatric tumors with a histologic diagnosis of glioblastoma multiforme, but with the molecular characteristics of other pediatric gliomas. For example, one study found that approximately 14% of patients with a diagnosis of glioblastoma multiforme had molecular characteristics that are associated with pleomorphic xanthoastrocytomas (e.g., high rates of V600E mutations).

Infants and young children with a glioblastoma multiforme diagnosis appear to have tumors with distinctive molecular characteristics when compared with tumors of older children. One report that applied DNA methylation analysis to glioblastoma multiforme tumors observed a group of patients (representing approximately 7% of pediatric patients with a histologic diagnosis of glioblastoma multiforme) whose tumors had molecular characteristics consistent with low-grade gliomas. The median age for this group of patients was 1 year, and they showed a favorable prognosis (3-year overall survival, approximately 90%). A second report investigated gene copy number gains and losses and mutation status of selected genes for glioblastoma multiforme tumors from children younger than 36 months. Molecular alterations observed at appreciable rates in older children (e.g., K27M, loss, amplification, and promoter mutations) were rare in the tumors of these young children, and novel abnormalities (e.g., loss of on chromosome 14q32) were observed in some cases.

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 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had V600E mutations, with alterations present in 8 of 14 cases (57%).

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

Diffuse Midline Glioma, H3 K27M-Mutant (Including Diffuse Intrinsic Pontine Gliomas [DIPGs])

The diffuse midline glioma, -mutant, category includes tumors previously classified as DIPG; most of the data is derived from experience with DIPG. This category also includes gliomas with the mutation arising in midline structures such as the thalamus.

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. The molecular and clinical characteristics of DIPGs align with those of other midline high-grade gliomas with a specific mutation in histone H3.1 () or H3.3 ( and ), which led the World Health Organization to group these tumors together into a single entity. In one report of 64 children with thalamic tumors, 50% of high-grade gliomas (11 of 22) had an mutation, and approximately 10% of tumors with low-grade morphological characteristics (5 of 42) had an mutation. Five-year overall survival (OS) was only 6% (1 of 16). In another study that included 202 children with glioblastoma, 68 of the tumors were midline (primarily thalamic) and had an mutation. Five-year OS for this group was only 5%, which was significantly inferior to the survival rates of the remaining patients in the study.

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 () or H3.3 ( and ) genes. This mutation is observed in pediatric high-grade gliomas at other midline locations but is uncommon in cortical pediatric high-grade gliomas and in adult high-grade gliomas. An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that the mutation was invariably present, supporting its role as a driver mutation for DIPG.
  • Activin A receptor, type I () gene: Approximately 20% of DIPG cases have activating mutations in the gene, with most occurring concurrently with H3.3 mutations. Germline mutations in cause the autosomal dominant syndrome fibrodysplasia ossificans progressiva (FOP), although there is no cancer predisposition in FOP.
  • Receptor tyrosine kinase amplification: amplification occurs in approximately 30% of cases, with lower rates of amplification observed for some other receptor tyrosine kinases (e.g., and ). An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that amplification was variably present across these sites, suggesting that this change is a secondary genomic alteration in DIPG.
  • deletion: DIPG tumors commonly show deletion of the gene on chromosome 17p. Additionally, is commonly mutated in DIPG tumors, particularly those with histone H3 gene mutations. Aneuploidy is commonly observed in cases with mutations.

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. Pediatric -mutant tumors rarely show MGMT promoter methylation, which explains the lack of efficacy of temozolomide when it was tested in patients with DIPG.

(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)

SMARCB1 gene

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

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

The 2016 WHO classification defines AT/RT by the presence of either or alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed .

Despite the absence of recurring genomic alterations beyond (and, more rarely, other SWI/SNF complex members), biologically distinctive subsets of AT/RT have been identified. 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:

  • AT/RT TYR: This subset represented approximately one-third of cases and was characterized by elevated expression of melanosomal markers such as (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. For patients with AT/RT TYR, the mean overall survival (OS) is 37 months (95% confidence interval [CI], 18–56 months). Cribriform neuroepithelial tumor is a brain cancer that also presents in young children and has genomic and epigenomic characteristics that are very similar to AT/RT TYR.
  • 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., and ). 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. For patients with AT/RT SHH, the mean OS is 16 months (95% CI, 8–25 months).
  • 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 were the most common mechanism of SMARCB1 loss for this subset. For patients with AT/RT MYC, the mean OS is 13 months (95% CI, 5–22 months).

In addition to somatic mutations, germline mutations in have been reported in a substantial subset of AT/RT patients. A study of 65 children with rhabdoid tumors found that 23 (35%) had germline mutations and/or deletions of . Children with germline alterations in presented at an earlier age than did sporadic cases (median age, approximately 5 months vs. 18 months) and were more likely to present with multiple tumors. One parent was found to be a carrier of the germline abnormality in 7 of 22 evaluated cases showing germline alterations, with four of the carrier parents being unaffected by -associated cancers. 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 alterations, but both parents lack a mutation/deletion. Screening children diagnosed with AT/RT for germline mutations may provide useful information for counseling families on the genetic implications of their child’s AT/RT diagnosis.

(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.)


Multiple medulloblastoma subtypes have been identified by integrative molecular analysis. Since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes and within different regions of the same tumor. However, different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy. These subtypes remain stable across primary and metastatic components. Further subclassification within these subgroups is possible, which will provide even more prognostic information. The 2016 World Health Organization (WHO) classification has endorsed this consensus by adding the following categories for genetically defined medulloblastoma:

  • Medulloblastoma, WNT-activated.
  • Medulloblastoma, sonic hedgehog (SHH)-activated and -mutant.
  • Medulloblastoma, SHH-activated and -wildtype.
  • Medulloblastoma, non-WNT/non-.

The following four core molecularly defined subtypes of medulloblastoma have been identified:

  • 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 tumors and rarely have a large cell/anaplastic appearance. They are infrequently metastasized at diagnosis. Genetically, these tumors have 6q loss (monosomy 6), mutations, and activated WNT signaling; MYC overexpression may be seen occasionally.

    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 mutations.

  • 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 , , , , and .

    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, mutation, and the finding of large cell/anaplastic histology. 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 , , and , have a more favorable prognosis than do patients with downstream genomic aberrations, such as and amplification. 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 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.

    The 2016 WHO classification identifies SHH medulloblastoma with a mutation as a distinctive entity (medulloblastoma, SHH-activated and -mutant). Approximately 25% of SHH-activated medulloblastoma cases have mutations, with a high percentage of these cases also showing a germline mutation (9 of 20 in one study). These patients are commonly between the ages of 5 years and 18 years and have an inferior outcome (overall survival at 5 years, <50%). The tumors often show large cell anaplastic histology.

  • 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, 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 amplification or 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. However, patients with group 3 medulloblastoma without amplification or overexpression who are older than 3 years have a prognosis similar to that of most patients with medulloblastoma, with a 5-year progression-free survival (PFS) rate higher than 70%.

  • 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 amplification, 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.

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. The classification of medulloblastoma into the four major subtypes will be altered in the future. 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.

Whether the classification for adults with medulloblastoma has similar predictive ability in children is unknown. In one study of adult medulloblastoma, 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.

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

Nonmedulloblastoma Embryonal Tumors

This section describes the genomic characteristics of embryonal tumors other than medulloblastoma and atypical teratoid/rhabdoid tumor. The 2016 WHO classification removed the term from the diagnostic lexicon. This change resulted from the recognition that many tumors previously classified as CNS PNETs have the common finding of amplification of the C19MC region on chromosome 19. These entities included ependymoblastoma, embryonal tumors with abundant neuropil and true rosettes (ETANTR), and some cases of medulloepithelioma. The 2016 WHO classification now categorizes tumors with C19MC amplification as , . Tumors previously classified as CNS PNETs are now termed , with the recognition that tumors in this category will likely be classified by their defining genomic lesions in future editions of the WHO classification.

A study applying unsupervised clustering of DNA methylation patterns for 323 nonmedulloblastoma embryonal tumors found that approximately one-half of these tumors diagnosed as nonmedulloblastoma embryonal tumors showed molecular profiles characteristic of other known pediatric brain tumors (e.g., high-grade glioma, atypical teratoid/rhabdoid tumor). 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 nonmedulloblastoma embryonal tumors, 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. 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.

    ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between and . This gene fusion puts expression of C19MC under control of the promoter, leading to high-level aberrant expression of the microRNAs within the cluster. The World Health Organization (WHO) allows histologically similar tumors without alteration to be classified as ETMR.

  • 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. 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 . There is no single genomic alteration among CNS NB-FOXR2 tumors leading to FOXR2 overexpression, with gene fusions involving multiple partners identified. This subtype has not been added to the WHO diagnostic lexicon.
  • CNS Ewing sarcoma family tumor with alteration (CNS EFT-CIC): Representing 4% of the 323 cases, this subtype is characterized by genomic alterations affecting (located on chromosome 19q13.2), with fusion to being identified in several cases tested. 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. CNS EFT-CIC tumors generally occur in children younger than 10 years and are characterized by a small cell phenotype but with variable histology. This subtype has not been added to the WHO diagnostic lexicon.
  • CNS high-grade neuroepithelial tumor with alteration (CNS HGNET-MN1): Representing 3% of the 323 cases, this subtype is characterized by gene fusions involving (located on chromosome 22q12.3), with fusion partners including and . This subtype shows a striking female predominance and tends to occur in the second decade of life. This subtype contained most cases carrying a diagnosis of astroblastoma as per the 2007 WHO classification scheme. This subtype has not been added to the WHO diagnostic lexicon.
  • CNS high-grade neuroepithelial tumor with alteration (CNS ): Representing 3% of the 323 cases, this subtype is characterized by internal tandem duplications of , a genomic alteration that is also found in clear cell sarcoma of the kidney. While the median age at diagnosis is younger than 10 years, cases arising in the second decade of life and beyond do occur. This subtype has not been added to the WHO diagnostic lexicon.


Medulloepithelioma is identified as a histologically discrete tumor within the WHO classification system. Medulloepithelioma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneurally, along nerve roots. Medulloepithelioma with the classic molecular change is considered an ETMR.


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 embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the () gene and in , as described below:

  • Pineoblastoma is associated with germline mutations in , with the term 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. Rates of pineoblastoma among children with heritable retinoblastoma who undergo current treatment programs may be lower than these historical estimates.
  • Germline mutations have also been reported in patients with pineoblastoma. Among 18 patients with pineoblastoma, three patients with germline mutations were identified, and an additional three patients known to be carriers of germline mutations developed pineoblastoma. The 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.

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


Molecular characterization studies have identified several biological subtypes of ependymoma based on their distinctive DNA methylation and gene expression profiles and on their distinctive spectrum of genomic alterations.

  • Infratentorial tumors.
    • Posterior fossa A, CpG island methylator phenotype (CIMP)-positive ependymoma, termed EPN-PFA.
    • Posterior fossa B, CIMP-negative ependymoma, termed EPN-PFB.
  • Supratentorial tumors.
    • -–positive ependymoma.
    • -–negative and fusion–positive ependymoma.
  • Spinal tumors.

Graph showing key molecular and clinical characteristics of ependymal tumor subgroups.Figure 6. Graphical summary of key molecular and clinical characteristics of ependymal tumor subgroups.Schematic representation of key genetic and epigenetic findings in the nine molecular subgroups of ependymal tumors as identified by methylation profiling. CIN, Chromosomal instability. Reprinted from Cancer Cell, Volume 27, Kristian W. Pajtler, Hendrik Witt, Martin Sill, David T.W. Jones, Volker Hovestadt, Fabian Kratochwil, Khalida Wani, Ruth Tatevossian, Chandanamali Punchihewa, Pascal Johann, Juri Reimand, Hans-Jorg Warnatz, Marina Ryzhova, Steve Mack, Vijay Ramaswamy, David Capper, Leonille Schweizer, Laura Sieber, Andrea Wittmann, Zhiqin Huang, Peter van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Daniel Fults, Helen Toledano, Smadar Avigad, Lindsey M. Hoffman, Andrew M. Donson, Nicholas Foreman, Ekkehard Hewer, Karel Zitterbart, Mark Gilbert, Terri S. Armstrong, Nalin Gupta, Jeffrey C. Allen, Matthias A. Karajannis, David Zagzag, Martin Hasselblatt, Andreas E. Kulozik, Olaf Witt, V. Peter Collins, Katja von Hoff, Stefan Rutkowski, Torsten Pietsch, Gary Bader, Marie-Laure Yaspo, Andreas von Deimling, Peter Lichter, Michael D. Taylor, Richard Gilbertson, David W. Ellison, Kenneth Aldape, Andrey Korshunov, Marcel Kool, and Stefan M. Pfister, Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups, Pages 728–743, Copyright (2015), with permission from Elsevier.

Approximately two-thirds of childhood ependymomas arise in the posterior fossa, and two major genomically defined subtypes of posterior fossa tumors are recognized. Similarly, most pediatric supratentorial tumors can be categorized into one of two genomic subtypes. These subtypes and their associated clinical characteristics are described below. Among these subtypes, the 2016 World Health Organization (WHO) classification has accepted ependymoma, fusion–positive as a distinct diagnostic entity.

The most common posterior fossa ependymoma subtype is EPN-PFA and is characterized by the following:

  • Presentation in young children (median age, 3 years).
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.
  • A balanced chromosomal profile (refer to Figure 7) with few chromosomal gains or losses.

    Chart showing the identification of subgroup-specific copy number alterations in the posterior fossa ependymoma genome.Figure 7. Identification of Subgroup-Specific Copy Number Alterations in the Posterior Fossa Ependymoma Genome. (A) Copy number profiling of 75 PF ependymomas using 10K array-CGH identifies disparate genetic landscapes between Group A and Group B tumors. Toronto and Heidelberg copy number datasets have been combined and summarized in a heatmap. The heatmap also displays the association of tumors to cytogenetic risk groups 1, 2, and 3 (Korshunov et al., 2010). Statistically significant chromosomal aberrations (black boxes) are also displayed between both subgroups, calculated by Fisher's exact test. Witt H, Mack SC, Ryzhova M, et al.: Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 20 (2): 143-57, 2011, doi:10.1016/j.ccr.2011.07.007. Copyright © 2011 Elsevier Inc. All rights reserved.

  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately 25% of cases.
  • Presence of the CIMP (i.e., CIMP positive).
  • High rates of disease recurrence (33% progression-free survival [PFS] at 5 years) and low survival rates compared with other subtypes (68% at 5 years).

The EPN-PFB subtype is less common than the EPN-PFA subtype in children and is characterized by the following:

  • Presentation primarily in adolescents and young adults (median age, 30 years).
  • Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.
  • Numerous cytogenetic abnormalities (refer to Figure 7), primarily involving the gain/loss of whole chromosomes.
  • Absence of the CIMP (i.e., CIMP negative).
  • Favorable outcome in comparison to EPN-PFA, with 5-year PFS of 73% and overall survival (OS) of 100%.

The largest subset of pediatric supratentorial (ST) ependymomas are characterized by gene fusions involving , a transcriptional factor important in NF-κB pathway activity. This subtype is termed ST-EPN-RELA and is characterized by the following:

  • Represents approximately 70% of supratentorial ependymomas in children, and presents at a median age of 8 years.
  • Presence of fusions resulting from chromothripsis involving chromosome 11q13.1.
  • Evidence of NF-κB pathway activation at the protein and RNA level.
  • Low rates of mutations that affect protein structure and absence of recurring mutations outside of fusions.
  • Presence of homozygous deletions of , a known poor prognostic factor for ependymomas, in approximately 15% of cases.
  • Gain of chromosome 1q, a known poor prognostic factor for ependymomas, in approximately one-quarter of cases.
  • Unfavorable outcome in comparison to other ependymoma subtypes, with 5-year PFS of 29% and OS of 75%.
  • Supratentorial clear cell ependymomas with branching capillaries commonly show the fusion, and one series of 20 patients with a median age of 10.4 years showed a relatively favorable prognosis (5-year PFS of 68% and OS of 72%).

A second, less common subset of supratentorial ependymomas, termed ST-EPN-YAP1, has fusions involving and are characterized by the following:

  • Median age at diagnosis of 1.4 years.
  • Presence of a gene fusion involving , with being the most common fusion partner.
  • A relatively stable genome with few chromosomal changes other than the fusion.
  • Relatively favorable prognosis (although based on small numbers), with a 5-year PFS of 66% and OS of 100%.

Clinical implications of genomic alterations

The absence of recurring mutations in the EPN-PFA and EPN-PFB subtypes at diagnosis precludes using their genomic profiles to guide therapy. The and fusion genes present in supratentorial ependymomas are not directly targetable with agents in the clinic, but can provide leads for future research.

(Refer to the PDQ summary on Childhood Ependymoma Treatment for information about the treatment of childhood ependymoma.)

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.
  • Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is activating mutations/deletions involving exon 3. mutations have been reported in 70% of cases. Rare causes of WNT pathway activation include mutations in , , and ( seen only in cases associated with familial adenomatosis polyposis coli).
  • The frequency of mutations in hepatoblastoma specimens was reported to be 4 of 62 tumors (7%) in one study and 5 of 51 specimens (10%) in another study. 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, and .
  • Figure 8 shows the distribution of , , and mutations for hepatoblastoma.

    Chart showing the distribution of CTNNB1, APC, NFE2L2, and TERT mutations for hepatoblastoma.Figure 8. 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 and mutations.
  • 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 , a homolog of the molecular chaperone DNAJ, fused in frame with , the catalytic domain of protein kinase A.
  • 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. mutations were observed in two of four cases tested. mutations are also commonly observed in adults with hepatocellular carcinoma.

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



The genomic landscape of osteosarcoma is distinctive from that of other childhood cancers. It is characterized by an exceptionally high number of structural variants with relatively small numbers of single nucleotide variants in comparison to many adult cancers.

Key observations regarding the genomic landscape of osteosarcoma are summarized below:

  • The number of structural variants observed for osteosarcoma is very high, at more than 200 structural variants per genome, such that osteosarcoma has the most chaotic genome among childhood cancers. The Circos plots shown in Figure 9 illustrate the exceptionally high numbers of intra- and inter-chromosomal translocations that typify osteosarcoma genomes.

    Diagrams of osteosarcoma cases from the NCI TARGET project.Figure 9. Circos plots of osteosarcoma cases from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatments (TARGET) project. The red lines in the interior circle connect chromosome regions involved in either intra- or inter-chromosomal translocations. Osteosarcoma is distinctive from other childhood cancers because it has a large number of translocations. Credit: National Cancer Institute.

  • The number of mutations per osteosarcoma genome that affect protein sequence (approximately 25 per genome) is higher than that of some other childhood cancers (e.g., Ewing sarcoma and rhabdoid tumors) but is far below that for adult cancers such as melanoma and non-small cell lung cancer.
  • Genomic alterations in are present in most osteosarcoma cases, with a distinctive form of inactivation occurring by structural variations in the first intron of that lead to disruption of the gene. Other mechanisms of inactivation are also observed, including missense and nonsense mutations and deletions of the gene. The combination of these various mechanisms for loss of function leads to biallelic inactivation in most cases of osteosarcoma.
  • amplification is observed in a minority of osteosarcoma cases (approximately 5%), and provides another mechanism for loss of function.
  • is commonly inactivated in osteosarcoma, sometimes by mutation but more commonly by deletion.
  • Other genes with recurrent alterations in osteosarcoma include and . Additionally, pathway analysis showed that the PI3K/mammalian target of rapamycin (mTOR) pathway was altered by mutation/loss/amplification in approximately one-fourth of patients, with mutation/loss being the most common alteration.
  • The range of mutations reported for osteosarcoma tumors at diagnosis do not provide obvious therapeutic targets, as they primarily reflect loss of tumor suppressor genes (e.g., , , ) rather than activation of targetable oncogenes.

A number of germline mutations are associated with susceptibility to osteosarcoma; Table 1 summarizes the syndromes and associated genes for these conditions. Mutations in are the most common germline alterations associated with osteosarcoma. Mutations in this gene are found in approximately 70% of patients with Li-Fraumeni syndrome (LFS), which is associated with increased risk of osteosarcoma, breast cancer, various brain cancers, soft tissue sarcomas, and other cancers. While rhabdomyosarcoma is the most common sarcoma arising in patients aged 5 years and younger with -associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years. One study observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%), with an overall mutation frequency of 9.5%. Another study observed germline mutations in in 7 of 59 (12%) osteosarcoma cases subjected to whole-exome sequencing. Other groups have reported lower rates (3%–7%) of germline mutations in patients with osteosarcoma.

Refer to the following summaries for more information about these genetic syndromes:

  • Genetics of Breast and Gynecologic Cancers (Li-Fraumeni syndrome).
  • Genetics of Skin Cancer (Bloom syndrome, Rothmund-Thomson syndrome, and Werner syndrome).

(Refer to the PDQ summary on Osteosarcoma and Malignant Fibrous Histiocytoma Treatment for information about the treatment of osteosarcoma.)

Ewing Sarcoma

The detection of a translocation involving the 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 2). The gene is a member of the TET family [TLS/EWS/TAF15] of RNA-binding proteins. The gene is a member of the ETS family of DNA-binding genes. Characteristically, the amino terminus of the gene is juxtaposed with the carboxy terminus of the family gene. In most cases (90%), the carboxy terminus is provided by , a member of the family of transcription factor genes located on chromosome 11 band q24. Other family members that may combine with the gene are , , (also termed ), and . Rarely, , another TET family member, can substitute for . Finally, there are a few rare cases in which has translocated with partners that are not members of the family of oncogenes. The significance of these alternate partners is not known.

Besides these consistent aberrations involving the 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.

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. These papers also identified mutations in , 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. deletions were noted in 12% to 22% of cases. Finally, mutations were identified in about 6% to 7% of cases and the coexistence of and mutations is associated with a poor clinical outcome.

Figure 10 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 deletion and mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.

Chart showing a comprehensive profile of the genetic abnormalities in Ewing sarcoma and associated clinical information.Figure 10. 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 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly. This test result must be considered with caution, however. Ewing sarcomas that utilize the translocations will have negative tests because the gene is not translocated in those cases. In addition, other small round tumors also contain translocations of different family members with , such as desmoplastic small round cell tumor, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and myxoid liposarcoma, all of which may be positive with a fluorescence hybridization (FISH) break-apart probe. A detailed analysis of 85 patients with small round blue cell tumors that were negative for rearrangement by FISH with an break-apart probe identified eight patients with rearrangements. Four patients who had fusions were not detected by FISH with an break-apart probe. The authors do not recommend relying solely on break-apart probes for analyzing small round blue cell tumors with strong immunohistochemical positivity for CD99.

Small round blue cell tumors of bone and soft tissue that are histologically similar to Ewing sarcoma but do not have rearrangements of the gene have been analyzed and translocations have been identified. These include , , and . The molecular profile of these tumors is different from the profile of 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.

A genome-wide association study identified a region on chromosome 10q21.3 associated with an increased risk of Ewing sarcoma. Deep sequencing through this region identified a polymorphism in the gene, which appears to cooperate with the gene product of the fusion that is seen in most patients with Ewing sarcoma. 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.

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


The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning risk group, determining therapy, and monitoring residual disease during treatment.

These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that fusion-positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors. In a study of Intergroup Rhabdomyosarcoma Study Group cases, which captured an entire cohort from a single prospective clinical trial, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases. The outcome was similar to that seen in patients with embryonal rhabdomyosarcoma and demonstrated that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.

(Refer to the PDQ summary on Childhood Rhabdomyosarcoma Treatment for information about the treatment of childhood rhabdomyosarcoma.)

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. 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 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. However, a subset appeared to be clonal, as an analysis of mutations showed that a significant proportion of patients (25%–30%) have evidence for mutant V600E.

BRAF-RAS pathwayFigure 11. 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 oncogene (V600E) that was detected in 35 (57%) of 61 cases. Multiple subsequent reports have confirmed the presence of V600E mutations in 50% or more of LCH cases in children. Another mutation ( 600DLAT) was identified, which resulted in the insertion of four amino acids and also appeared to activate signaling. mutations are infrequent in LCH, but when present, can also lead to RAS-MAPK pathway activation. No clinical characteristics associated with the V600E mutation have been identified.

The RAS-MAPK signaling pathway (Figure 11) 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 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.

Because RAS-MAPK pathway activation can be detected in all LCH cases, but not all cases have mutations, the presence of genomic alterations in other components of the pathway was suspected. Whole-exome sequencing of -mutated versus –wild-type LCH biopsies revealed that 7 of 21 –wild-type specimens had mutations, while no -mutated specimens had mutations. The mutations in (which codes for MEK) were activating, as indicated by their induction of ERK phosphorylation. Another study showed mutations exclusively in 11 of 22 –wild-type cases. Finally, in-frame deletions and in-frame fusions have occurred in the group of V600E and mutation–negative cases. Studies to date support the universal activation of ERK in LCH, with activation in most cases being explained by and alterations.

The presence of V600E mutation in blood and bone marrow was studied in a series of 100 patients, of which 65% tested positive for the V600E mutation by a sensitive quantitative polymerase chain reaction technique. Circulating cells with the 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.

A study of 173 patients with the V600E mutation, and 142 patients without the mutation, revealed that the mutation occurred in 88% of patients with high-risk disease, 69% of patients with multisystem low-risk LCH, and 44% of patients with single-system low-risk LCH. The mutation was also found in 75% of patients with neurodegenerative syndrome and 73% of patients with pituitary involvement. Resistance to initial treatment and relapse were higher in patients with the mutation.

Clinical implications

Clinical implications of the described genomic findings include the following:

  • LCH joins a group of other pediatric entities with activating mutations, including select nonmalignant conditions (e.g., benign nevi) and low-grade malignancies (e.g., pilocytic astrocytoma). 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.
  • 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. The most serious side effect of BRAF inhibitors is the induction of cutaneous squamous cell carcinomas, with the incidence of these second cancers increasing with age; reduction of this side effect can occur with concurrent treatment with both BRAF and MEK inhibitors. Case reports have described activity of BRAF inhibitors against LCH in adult and pediatric 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 V600E (or potentially mutated ) in circulating cells may become a useful diagnostic tool to define high-risk versus low-risk disease. Additionally, for patients who have a somatic mutation, persistence of circulating cells with the mutation may be useful as a marker of residual disease.

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


Neuroblastoma can be subdivided into a biologically defined subset that has a very favorable prognosis (i.e., low-risk neuroblastoma) and another group that has a guarded prognosis (i.e., high-risk neuroblastoma). While neuroblastoma in infants with tumors that have favorable biology is highly curable, only 50% of children with high-risk neuroblastoma are alive at 5 years from diagnosis, at best.

Low-risk neuroblastoma is usually found in children younger than 18 months with limited extent of disease; the tumor has changes, usually increases, in the number of whole chromosomes in the neuroblastoma cell. Low-risk tumors are hyperdiploid when examined by flow cytometry. In contrast, high-risk neuroblastoma generally occurs in children older than 18 months, is often metastatic to bone, and usually has segmental chromosome abnormalities. They are near diploid or near tetraploid by flow cytometric measurement. High-risk tumors also show exonic mutations (refer to the Exonic mutations in neuroblastoma section of this summary for more information), but most high-risk tumors lack mutations in genes that are recurrently mutated. Compared with adult cancers, neuroblastomas show a low number of mutations per genome that affect protein sequence (10–20 per genome).

Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:

  • Segmental chromosomal aberrations, including gene amplification.
  • Low rates of exonic mutations, with activating mutations in being the most common recurring alteration.
  • Genomic alterations that promote telomere lengthening.

Segmental chromosomal aberrations (including MYCN gene amplification)

Segmental chromosomal aberrations, found most frequently in 1p, 1q, 3p, 11q, 14q, and 17p (and amplification), are best detected by comparative genomic hybridization and are seen in almost all high-risk and/or stage 4 neuroblastomas. Among all patients with neuroblastoma, a higher number of chromosome breakpoints correlated with the following, whether or not amplification was considered:[]

  • Advanced age at diagnosis.
  • Advanced stage of disease.
  • Higher risk of relapse.
  • Poorer outcome.

In a study of unresectable primary neuroblastomas without metastases in children older than 12 months, segmental chromosomal aberrations were found in most, and older children were more likely to have them and to have more of them per tumor cell. In children aged 12 to 18 months, the presence of segmental chromosomal aberrations had a significant effect on event-free survival (EFS) but not on overall survival (OS). However, in children older than 18 months, there was a significant difference in OS in children with segmental chromosomal aberrations versus children without segmental chromosomal aberrations (67% vs. 100%), regardless of the histologic prognosis.

Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without gene amplification.

amplification (defined as more than 10 copies per diploid genome) is one of the most common segmental chromosomal aberrations, detected in 16% to 25% of tumors. For high-risk neuroblastoma, 40% to 50% of cases show amplification. In all stages of disease, amplification of the gene strongly predicts a poorer prognosis in both time to tumor progression and OS in almost all multivariate regression analyses of prognostic factors. Within the localized -amplified cohort, ploidy status may further predict outcome. However, patients with hyperdiploid tumors with any segmental chromosomal aberrations do relatively poorly.

Most unfavorable clinical and pathobiological features are associated, to some degree, with amplification; in a multivariable logistic regression analysis of 7,102 International Neuroblastoma Risk Group patients, pooled segmental chromosomal aberrations and gain of 17q were the only poor prognostic features not associated with amplification. However, segmental chromosomal aberrations at 11q are almost mutually exclusive of diffuse amplification.

Exonic mutations in neuroblastoma

Multiple reports have documented that a minority of high-risk neuroblastomas have a small number of low-incidence, recurrently mutated genes. The most commonly mutated gene is , which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutation include , , , and . As shown in Figure 12, most neuroblastoma cases lack mutations in genes that are altered in a recurrent manner.

Chart showing the landscape of genetic variation in neuroblastoma.Figure 12. Data tracks (rows) facilitate the comparison of clinical and genomic data across cases with neuroblastoma (columns). The data sources and sequencing technology used were whole-exome sequencing (WES) from whole-genome amplification (WGA) (light purple), WES from native DNA (dark purple), Illumina WGS (green), and Complete Genomics WGS (yellow). Striped blocks indicate cases analyzed using two approaches. The clinical variables included were sex (male, blue; female, pink) and age (brown spectrum). Copy number alterations indicates ploidy measured by flow cytometry (with hyperdiploid meaning DNA index >1) and clinically relevant copy number alterations derived from sequence data. Significantly mutated genes are those with statistically significant mutation counts given the background mutation rate, gene size, and expression in neuroblastoma. Germline indicates genes with significant numbers of germline ClinVar variants or loss-of-function cancer gene variants in our cohort. DNA repair indicates genes that may be associated with an increased mutation frequency in two apparently hypermutated tumors. Predicted effects of somatic mutations are color coded according to the legend. Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (Pugh TJ, Morozova O, Attiyeh EF, et al.: The genetic landscape of high-risk neuroblastoma. Nat Genet 45 (3): 279-84, 2013), copyright (2013).

, the exonic mutation found most commonly in neuroblastoma, is a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. Germline mutations in have been identified as the major cause of hereditary neuroblastoma. Somatically acquired -activating mutations are also found as oncogenic drivers in neuroblastoma.

The presence of an mutation correlates with significantly poorer survival in high-risk and intermediate-risk neuroblastoma patients. mutation was examined in 1,596 diagnostic neuroblastoma samples. tyrosine kinase domain mutations occurred in 8% of samples—at three hot spots and 13 minor sites—and correlated significantly with poorer survival in patients with high-risk and intermediate-risk neuroblastoma. mutations were found in 10.9% of -amplified tumors versus 7.2% of those without amplification. mutations occurred at the highest frequency (11%) in patients older than 10 years. The frequency of aberrations was 14% in the high-risk neuroblastoma group, 6% in the intermediate-risk neuroblastoma group, and 8% in the low-risk neuroblastoma group.

Small-molecule ALK kinase inhibitors such as crizotinib are being developed and tested in patients with recurrent and refractory neuroblastoma. (Refer to the Treatment Options Under Clinical Evaluation for Recurrent or Refractory Neuroblastoma section in the PDQ summary on Neuroblastoma Treatmentfor more information about crizotinib clinical trials.)

Genomic evolution of exonic mutations

There are limited data regarding the genomic evolution of exonic mutations from diagnosis to relapse for neuroblastoma. Whole-genome sequencing was applied to 23 paired diagnostic and relapsed neuroblastomas to define somatic genetic alterations associated with relapse, while a second study evaluated 16 paired diagnostic and relapsed specimens. Both studies identified an increased number of mutations in the relapsed samples compared with the samples at diagnosis.

  • The first study found increased incidence of mutations in genes associated with RAS-MAPK signaling at relapse than at diagnosis, with 15 of 23 relapse samples containing somatic mutations in genes involved in this pathway and each mutation consistent with pathway activation.

    In addition, three relapse samples showed structural alterations involving MAPK pathway genes consistent with pathway activation, so aberrations in this pathway were detected in 18 of 23 relapse samples (78%). Aberrations were found in (n = 10), (n = 2), and one each in , , , , , and . Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutation presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.

  • In the second study, mutations were not observed in either diagnostic or relapse specimens, but relapse-specific recurrent single-nucleotide variants were observed in 11 genes, including the putative neuroblastoma tumor suppressor gene located at chromosome 1p36.

In a study of 276 neuroblastoma samples of all stages and from patients of all ages, very deep (33,000X) sequencing of two amplified mutational hot spots revealed 4.8% clonal mutations and an additional 5% subclonal mutations, suggesting that subclonal mutations are common. Deep sequencing can reveal the presence of mutations in tiny subsets of tumor cells that may be able to survive during treatment and grow to constitute a relapse.

Genomic alterations promoting telomere lengthening

Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, resulting eventually in the lack of a cell’s ability to replicate. Low-risk neuroblastomas have little telomere lengthening activity. Aberrant genetic mechanisms for telomere lengthening have been identified for high-risk neuroblastoma. Thus far, the following three mechanisms, which appear to be mutually exclusive, have been described:

  • Chromosomal rearrangements involving a chromosomal region at 5p15.33 proximal to the gene, which encodes the catalytic unit of telomerase, occur in approximately 25% of high-risk neuroblastoma cases and are mutually exclusive with amplifications and mutations. The rearrangements induce transcriptional upregulation of by juxtaposing the coding sequence with strong enhancer elements.
  • Another mechanism promoting overexpression is amplification, which is associated with approximately 40% to 50% of high-risk neuroblastomas.
  • The mutation or deletion is found in 10% to 20% of high-risk neuroblastomas, almost exclusively in older children, and is associated with telomere lengthening by a different mechanism, termed .

Additional biological factors associated with prognosis

MYC and MYCN expression

Immunostaining for MYC and MYCN proteins on 357 undifferentiated/poorly differentiated neuroblastomas has demonstrated that elevated MYC/MYCN protein expression is prognostically significant. Sixty-eight tumors highly expressed MYCN protein, and 81 were amplified. Thirty-nine tumors expressed MYC highly and were mutually exclusive of high MYCN expression. Segmental chromosomal aberrations were not examined in this study, except for amplification.

  • Patients with favorable-histology (FH) tumors without high MYC/MYCN expression had favorable survival (3-year EFS, 89.7% ± 5.5%; 3-year OS, 97% ± 3.2%).
  • Patients with undifferentiated or poorly differentiated histology tumors without MYC/MYCN expression had a 3-year EFS rate of 63.1% ± 13.6% and a 3-year OS rate of 83.5% ± 9.4%.
  • Three-year EFS rates in patients with amplification, high MYCN expression, and high MYC expression were 48.1% ± 11.5%, 46.2% ± 12%, and 43.4% ± 23.1%, respectively, and OS rates were 65.8% ± 11.1%, 63.2% ± 12.1%, and 63.5% ± 19.2%, respectively.
  • Further, when high expression of MYC and MYCN proteins were analyzed with other prognostic factors, including gene amplification, high MYC and MYCN protein expression was independent of other prognostic markers.

Most neuroblastomas with amplification in the International Neuroblastoma Pathology Classification system have unfavorable histology, but about 7% have FH. Of those with amplification and FH, most do not express MYCN, despite the gene being amplified, and have a more favorable prognosis than those that express MYCN. Segmental chromosomal aberration at 11q is almost mutually exclusive of diffuse amplification. Rarely, amplification may be detected by fluorescence hybridization in only a subclone of the tumor cells. In these cases, the clinical outcome reflects the prognostic background (i.e., age, stage, ploidy, and segmental chromosomal aberrations) of the tumor in which the heterogeneous amplification is found.

Neurotrophin receptor kinases

Expression of neurotrophin receptor kinases and their ligands vary between high-risk and low-risk tumors. TrkA is found on low-risk tumors, and absence of its ligand NGF is postulated to lead to spontaneous tumor regression. In contrast, TrkB is found in high-risk tumors that also express its ligand, BDNF, which promotes neuroblastoma cell growth and survival.

Immune system inhibition

Anti-GD2 antibodies, along with modulation of the immune system to enhance antineuroblastoma activity, are often used to help treat neuroblastoma. The anti-GD2 antibody (3F8), used for treating neuroblastoma exclusively at one institution, utilizes natural killer cells to kill the neuroblastoma cells. However, the natural killer cells can be inhibited by the interaction of HLA antigens and killer immunoglobulin receptor subtypes. Thus, the patient's immune system genes can help determine response to immunotherapy for neuroblastoma. A report on the effects of immune system genes on response to dinutuximab, a commercially available anti-GD2 antibody, awaits publication.

(Refer to the PDQ summary on Neuroblastoma Treatment for information about the treatment of neuroblastoma.)


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 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 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as and polymorphisms. 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.

The genomic landscape of retinoblastoma is driven by alterations in that lead to biallelic inactivation. A rare cause of inactivation is chromothripsis, which may be difficult to detect by conventional methods. Other recurring genomic changes that occur in a small minority of tumors include mutation/deletion, amplification, and amplification. A study of 1,068 unilateral nonfamilial retinoblastoma tumors reported that a small percentage of cases (approximately 3%) lacked evidence of loss. Approximately one-half of these cases with no evidence of loss (representing approximately 1.5% of all unilateral nonfamilial retinoblastoma) showed amplification.

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

Kidney Tumors

Wilms Tumor

Wilms tumor is thought to arise from clonal expansion of a nephrogenic rest. 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 () is the oncogenic driver. Approximately one-third of Wilms tumor cases involve mutations in , , or . Another subset of Wilms tumor cases result from mutations in miRNA processing genes (miRNAPG), including , , , and . Other genes that are recurrently mutated in Wilms tumor include and (transcription factors that play key roles in early renal development) and (a gene involved in transcriptional elongation in early development). Anaplastic Wilms tumor is characterized by the presence of 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. Other genetic causes that have been observed in familial Wilms tumor cases include germline mutations in and .

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

Wilms tumor 1 gene (WT1)

The 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. mutations are observed in 10% to 20% of cases of sporadic Wilms tumor.

Wilms tumor with a mutation is characterized by the following:

  • Evidence of WNT pathway activation by activating mutations in the gene () is common.
  • Loss of heterozygosity at 11p15 is commonly observed, as paternal uniparental disomy for chromosome 11 represents a common mechanism for losing the remaining normal allele.
  • Nephrogenic rests are benign foci of embryonal kidney cells that abnormally persist into postnatal life. Intralobar nephrogenic rests occur in approximately 20% of Wilms tumor cases. They are observed at high rates in cases with genetic syndromes that have mutations such as WAGR and Denys-Drash syndromes. Intralobar nephrogenic rests are also observed in cases with sporadic and mutations.
  • germline mutations are uncommon (2%–4%) in nonsyndromic Wilms tumor.
  • 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. These findings need validation but may provide biomarkers for stratifying patients in the future.

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

  • WAGR syndrome, Denys-Drash syndrome, or Frasier syndrome.
  • 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 mutations include WAGR syndrome, Denys-Drash syndrome, and Frasier syndrome.

  • 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 and genes.

    Inactivating mutations or deletions in the gene lead to aniridia, while deletion of confers the increased risk of Wilms tumor. Sporadic aniridia in which 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 gene and are not at an increased risk of Wilms tumor.

    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. The mental retardation in WAGR syndrome may be secondary to deletion of other genes, including or .

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

  • 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.

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

    Studies evaluating genotype/phenotype correlations of 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%). Bilateral Wilms tumor was more common in cases with -truncating mutations (9 of 14 cases) than in cases with missense mutations (3 of 27 cases). These genomic studies confirm previous estimates of elevated risk of Wilms tumor for children with Denys-Drash syndrome and low risk of Wilms tumor for children with Frasier syndrome.

Late effects associated with WAGR syndrome and Wilms tumor include the following:

  • Children with WAGR syndrome or other germline mutations are monitored throughout their lives because they are at increased risk of developing hypertension, nephropathy, and renal failure.
  • Patients with Wilms tumor and aniridia without genitourinary abnormalities are at lower risk but are monitored for nephropathy or renal failure.
  • Children with Wilms tumor and any genitourinary anomalies are also at increased risk of late renal failure and are monitored. Features associated with germline mutations that increase the risk of developing renal failure include the following:
    • Stromal predominant histology.
    • Bilateral disease.
    • Intralobar nephrogenic rests.
    • Wilms tumor diagnosed before age 2 years.

(Refer to the Late effects after Wilms tumor therapy section of the PDQ summary on Wilms Tumor and Other Childhood Kidney Tumors Treatment for more information about the late effects associated with Wilms tumor.)

Beta-catenin gene (CTNNB1)

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

Wilms tumor gene on the X chromosome (WTX)

, which is also called , is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases. Germline mutations in cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (MIM300373). Despite having germline mutations, individuals with osteopathia striata congenita are not predisposed to tumor development. The WTX protein appears to be involved in both the degradation of beta-catenin and in the intracellular distribution of APC protein. is most commonly altered by deletions involving part or all of the gene, with deleterious point mutations occurring less commonly. Most Wilms tumor cases with alterations have epigenetic 11p15 abnormalities.

alterations are equally distributed between males and females, and inactivation has no apparent effect on clinical presentation or prognosis.

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

A second Wilms tumor locus, , 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 tumor 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.

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

Several candidate genes at the locus comprise the two independent imprinted domains and . 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.

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. 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.

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

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

Other genes and chromosomal alterations

Additional genes and chromosomal alterations that have been implicated in the pathogenesis and biology of Wilms tumor include the following:

  • 1q. Gain of chromosome 1q is associated with an inferior outcome and is the single most powerful predictor of outcome. In the presence of 1q gain, neither 1p nor 16q loss is significant. Gain of chromosome 1q is one of the most common cytogenetic abnormalities in Wilms tumor and is observed in approximately 30% of tumors.

    In an analysis of FH Wilms tumor from 1,114 patients from , 28% of the tumors displayed 1q gain.

    • The 8-year event-free survival (EFS) rate was 77% for patients with 1q gain and 90% for those lacking 1q gain ( < .001). Within each disease stage, 1q gain was associated with inferior EFS.
    • The 8-year overall survival (OS) rate was 88% for those with 1q gain and 96% for those lacking 1q gain ( < .001). OS was significantly inferior in cases with stage I disease ( < .0015) and stage IV disease ( = .011).
  • 16q and 1p. Additional tumor-suppressor or tumor-progression genes may lie on chromosomes 16q and 1p, as evidenced by loss of heterozygosity for these regions in 17% and 11% of Wilms tumor cases, respectively.
    • 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.
    • 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.

    These conflicting results may arise from the greater prognostic significance of 1q gain described above. Loss of heterozygosity of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, loss of heterozygosity of 16q and 1p retains their adverse prognostic impact. The loss of heterozygosity of 16q and 1p appears 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.

  • miRNAPG. Mutations in selected miRNAPG are observed in approximately 20% of Wilms tumor cases. The products of these genes direct the maturation of miRNAs from the initial pri-miRNA transcripts to functional cytoplasmic miRNAs (refer to Figure 13). The most commonly mutated miRNAPG is , with a recurrent mutation (E1147K) affecting a metal-binding residue of the RNase IIIb domain, representing about 80% of -mutated tumors. Other miRNAPG that are mutated in Wilms tumor include , , , , and . 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 (located on chromosome 22q11), with 38 of 43 cases (88%) arising in girls.

    Germline mutations in miRNAPG are observed for and , 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 , with tumor formation following acquisition of a missense mutation in a domain of the remaining allele of (the RNase IIIb domain) responsible for processing miRNAs derived from the 5p arms of pre-miRNAs. Tumors associated with DICER1 syndrome include pleuropulmonary blastoma, cystic nephroma, ovarian sex cord–stromal tumors, multinodular goiter, and embryonal rhabdomyosarcoma. Wilms tumor is an uncommon presentation of the DICER1 syndrome. In one study, three families with DICER1 syndrome included children with Wilms tumor, with two of the Wilms tumor cases showing the typical second mutation in the RNase IIIb domain. Another study identified mutations in 2 of 48 familial Wilms tumor families. Large sequencing studies of Wilms tumor cohorts have also observed occasional cases with mutations.
    • Perlman syndrome is a rare overgrowth disorder caused by mutations in , which encodes a ribonuclease that is responsible for degrading pre-let-7 miRNA. 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 patients showed developmental delay. Fetal macrosomia, ascites, and polyhydramnios are frequent manifestations.

      Diagram showing the miRNA processing pathway, which is commonly  mutated in Wilms' tumor.Figure 13. 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 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

  • and . and 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 mutations is 3% to 4% in Wilms tumor, and the frequency of mutations in Wilms tumor is 1% to 3%. Virtually all and mutations are in exon 1 and result in a glutamine-to-arginine mutation at position 177. Mutations in , , and are infrequent in cases with or miRNAPG mutations. Conversely, mutations and miRNAPG mutations tend to occur together.
  • . Approximately 4% of Wilms tumor cases have mutations in the highly conserved YEATS domain of (), a gene known to be involved in transcriptional elongation by RNA polymerase II during early development. The mutant MLLT1 protein shows altered binding to acetylated histone tails. Patients with -mutant tumors present at a younger age and have a high prevalence of precursor intralobar nephrogenic rests, supporting a model whereby activating mutations early in renal development result in the development of Wilms tumor.
  • (tumor suppressor gene). Most anaplastic Wilms tumor cases show mutations in the tumor suppressor gene. may be useful as an unfavorable prognostic marker. A study of 40 patients with diffuse anaplastic Wilms tumor identified 25 patients with alterations (22 with mutations with or without 17p loss, and 3 with only 17p loss). The 25 cases with alterations had a significantly lower EFS and OS than did those without alterations. Microdissection of focally anaplastic Wilms tumor demonstrated mutations in anaplastic but not nonanaplastic areas of the tumor, suggesting that acquisition of mutation may be inherent in the process of becoming anaplastic.
  • . , 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.
  • 9q22.3 microdeletion syndrome. Patients with 9q22.3 microdeletion syndrome have an increased risk of Wilms tumor. The chromosomal region with germline deletion includes , the gene that is mutated in Gorlin syndrome (nevoid basal cell carcinoma syndrome associated with osteosarcoma). 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. Five patients who presented with Wilms tumor in the context of a constitutional 9q22.3 microdeletion have been reported.
  • . 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%). Activating mutations at codon 44 (p.P44L) were identified in approximately 4% of Wilms tumor cases. Germline copy number gain at has been reported in a bilateral Wilms tumor case, and germline duplication was also reported for a child with prenatal bilateral nephroblastomatosis and a family history of nephroblastoma.
  • . Inactivating germline mutations were identified in 3 of 35 familial Wilms tumor pedigrees. , 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.
  • . Inactivating germline mutations in (encoding RE1-silencing transcription factor) were identified in four familial Wilms tumor pedigrees. REST is a transcriptional repressor that functions in cellular differentiation and embryonic development. Most mutations clustered within the portion of REST encoding the DNA-binding domain, and functional analyses showed that these mutations compromise REST transcriptional repression. When screened for mutations, 9 of 519 individuals with Wilms tumor who had no history of relatives with the disease tested positive for the mutation; some had parents who also tested positive. These observations indicate that is a Wilms tumor predisposition gene associated with approximately 2% of Wilms tumor.

Figure 14 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH. The 75 FH Wilms tumor cases were clustered by unsupervised analysis of gene expression data, resulting in six clusters. Five of six -mutant tumors with available gene expression data were in cluster 3, and two were accompanied by mutations. This cluster also contained four tumors with a mutation or small segment deletion of , all of which also had either a mutation of or small segment deletion or mutation of . It also contained a substantial number of tumors with retention of imprinting of 11p15 (including all -mutant tumors). The miRNAPG-mutated cases clustered together and were mutually exclusive with both and with //-mutated cases.

Chart showing unsupervised analysis of gene expression data for clinically distinctive favorable histology Wilms tumor.Figure 14. Unsupervised analysis of gene expression data. Non-negative Matrix Factorization (NMF) analysis of 75 FH Wilms tumor resulted in six clusters. Five of six MLLT1 mutant tumors with available gene expression data occurred in NMF cluster 3, and two were accompanied by CTNNB1 mutations. This cluster also contained a substantial number of tumors with retention of imprinting of 11p15 (including all MLLT1-mutant tumors), in contrast to other clusters, where most cases showed 11p15 loss of heterozygosity or retention of imprinting. Almost all miRNAPG-mutated cases were in NMF cluster 2, and most WT1, WTX, and CTNNB1 mutations were in NMF clusters 3 and 4. 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

Renal Cell Carcinoma

Translocation-positive carcinomas of the kidney are recognized as a distinct form of renal cell carcinoma (RCC) and may be the most common form of RCC in children, accounting for 40% to 50% of pediatric RCC. In a Children's Oncology Group (COG) prospective clinical trial of 120 childhood and adolescent patients with RCC, nearly one-half of patients had translocation-positive RCC. These carcinomas are characterized by translocations involving the gene located on Xp11.2. The gene may partner with one of the following genes:

  • in t(X;17)(p11.2;q25).
  • in t(X;1)(p11.2;q21).
  • in t(X;1)(p11.2;p34).
  • in inv(X;p11.2;q12).
  • in t(X;17)(p11;q23).

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

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.

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 more advanced stage (III/IV) than -RCC, a meta-analysis reported that these patients have poorer outcomes. The outcomes for these patients are being studied in the ongoing COG 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. Recurrences have been reported 20 to 30 years after initial resection of the translocation-associated RCC.

Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using immunohistochemistry alone, because reported cases have lacked the translocation. There is a rare subset of RCC cases that is positive for and lack a translocation, showing an translocation instead. This subset of cases represents a newly recognized subgroup within RCC that is estimated to involve 15% to 20% of unclassified pediatric RCC. In the eight reported cases in children aged 6 to 16 years, the following was observed:

  • was fused to () in a t(2;10)(p23;q22) translocation (n = 3). The translocation cases all occurred in children with sickle cell trait, whereas none of the translocation cases did.
  • was fused to () (n = 3).
  • was fused to on 1p32 (n = 1).
  • t(1;2) translocation fusing and (n = 1).

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

Germline mutations of 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. Approximately one-third of patients with rhabdoid tumors have germline alterations. 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). Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis. Germline mutations in have also been reported in patients with rhabdoid tumors.

(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 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. Other reports have confirmed the finding of internal tandem duplications in clear cell sarcoma of the kidney. Hence, 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.
  • The fusion (involving either or ) resulting from t(10;17) was reported in 12% of cases of clear cell sarcoma of the kidney. The presence of the fusion appears to be mutually exclusive with the presence of 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 fusion and 20 cases with internal tandem duplications. The gene expression profiles for cases with the fusion were distinctive from those with 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 fusion and 12 cases with internal tandem duplications. 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 internal tandem duplication as the primary oncogenic driver for clear cell sarcoma of the kidney.

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

  • 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 3.

The genomic landscape of conventional melanoma in children is represented by many of the genomic alterations found in adults with melanoma. A report from the Pediatric Cancer Genome Project observed that 15 cases of conventional melanoma had a high burden of somatic single-nucleotide variations, promoter mutations (12 of 13), and activating 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 variants associated with an increased susceptibility to melanoma.

The genomic landscape of spitzoid melanomas is characterized by kinase gene fusions involving various genes including , , , , , and . These fusion genes have been reported in approximately 50% of cases and occur in a mutually exclusive manner. 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 promoter mutations experienced hematogenous metastases and died of their disease. This finding supports the potential of promoter mutations in predicting aggressive clinical behavior in children with spitzoid melanocytic neoplasms, but further study is needed to define the role of wild-type promoter status in predicting clinical behavior in patients with primary site spitzoid tumors.

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

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

Thyroid Cancer

Studies have shown subtle differences between the genetic profiling of childhood differentiated thyroid carcinomas and that of adult tumors (refer to Table 4). In one study, a higher prevalence of rearrangements was reported in pediatric papillary carcinoma (45%–65% in children vs. 3%–34% in adults). V600E mutations are seen in more than 50% of adults with papillary thyroid carcinoma; although it likely occurs in a similar frequency in pediatric patients, studies have revealed a wide variation in frequency of this mutation. In children, the correlation between the genomic alteration and stage or prognosis has not been well defined. While two studies failed to show a correlation, one study that included 55 pediatric thyroid carcinoma cases demonstrated a significant correlation between the presence of a V600E mutation and an increased risk of recurrence. Differentiated thyroid carcinoma has been associated with germline mutations and it is considered part of the syndrome.

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

Multiple Endocrine Neoplasia Syndromes

The most salient clinical and genetic alterations of the multiple endocrine neoplasia (MEN) syndromes are shown in Table 5.

  • 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 5 are present.

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

    Germline mutations of the 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. Mutation testing is combined with clinical screening for patients and family members with proven at-risk MEN1 syndrome.

    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.

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

    A germline activating mutation in the 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. Table 6 describes the clinical features of MEN2A and MEN2B syndromes.

    • MEN2A: MEN2A is characterized by the presence of two or more endocrine tumors (refer to Table 5) in an individual or in close relatives. 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. 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. 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 mutations.

    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.

  • 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. 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 germline mutations; small families in which two or fewer members in a single generation have germline mutations; and single individuals with a germline mutation.

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

Changes to this Summary (08/18/2017)

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.


Revised text in the Acute Lymphoblastic Leukemia (ALL) subsection to state that the –like gene expression profile occurs in 10% to 20% of pediatric acute lymphoblastic leukemia patients, increasing in frequency with age, and has been associated with a poor prognosis and with deletion or mutation (cited Reshmi et al. as reference 93).

Added Schmäh et al. as reference 100 in the Acute Lymphoblastic Leukemia (ALL) subsection.

Central Nervous System Tumors

Revised text in the Medulloblastomas subsection to state that since 2012, the general consensus is that medulloblastoma can be molecularly separated into at least four core subtypes and within different regions of the same tumor. However, different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy (cited Morrissy et al. as reference 79).


Added text to the Neuroblastoma section to state that amplification may be detected by fluorescence hybridization in only a subclone of the tumor cells. In these cases, the clinical outcome reflects the prognostic background of the tumor in which the heterogeneous amplification is found (cited Bogen et al. and Berbegall et al. as references 26 and 27, respectively).

Kidney Tumors

Editorial changes were made to the Wilms Tumor subsection.

Thyroid Cancer

Editorial changes were made to this section.

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).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewer for Childhood Cancer Genomics is:

  • Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Cancer Genomics. Bethesda, MD: National Cancer Institute. Updated . Available at: Accessed . [PMID: 27466641]

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