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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:
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:
Another theme across multiple childhood cancers is the contribution of mutations of genes involved in normal development of the tissue of origin of the cancer and the contribution of genes involved in epigenomic regulation.
Structural variations play an important role for many childhood cancers. Translocations resulting in oncogenic fusion genes or overexpression of oncogenes play a central role, particularly for the leukemias and sarcomas. However, for other childhood cancers that are primarily characterized by structural variations, functional fusion genes are not produced. Mechanisms by which these recurring structural variations have oncogenic effects have been identified for osteosarcoma (translocations confined to the first intron of TP53) and medulloblastoma (structural variants juxtapose GFI1 or GFI1B coding sequences proximal to active enhancer elements leading to transcriptional activation [enhancer hijacking]).[
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.[
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)
Genomics of childhood ALL
The genomics of childhood acute lymphoblastic leukemia (ALL) has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics.[
Throughout this section, the percentages of genomic subtypes from among all B-ALL and T-ALL cases are derived primarily from a report describing the genomic characterization of patients treated on several Children's Oncology Group (COG) and St. Jude Children's Research Hospital (SJCRH) clinical trials. Percentages by subtype are presented for NCI standard-risk and NCI high-risk patients with B-ALL (up to age 18 years).[
B-ALL is typified by genomic alterations that include: 1) gene fusions that lead to aberrant activity of transcription factors, 2) chromosomal gains and losses (e.g., hyperdiploidy or hypodiploidy), and 3) alterations leading to activation of tyrosine kinase genes.[
Figure 1. Genomic subtypes and frequencies of NCI standard-risk B-ALL. The figure represents data from 1,126 children diagnosed with NCI standard-risk B-ALL (aged 1–9 years and WBC <50,000/µL) and enrolled in St. Jude Children's Research Hospital or Children's Oncology Group clinical trials. Adapted from Supplemental Table 2 of Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.
Figure 2. Genomic subtypes and frequencies of NCI high-risk B-ALL. The figure represents data from 1,084 children diagnosed with NCI high-risk B-ALL (aged 1–18 years and WBC >50,000/µL) and enrolled in St. Jude Children's Research Hospital or Children's Oncology Group clinical trials. Adapted from Supplemental Table 2 of Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.
The genomic landscape of B-ALL is characterized by a range of genomic alterations that disrupt normal B-cell development and, in some cases, by mutations in genes that provide a proliferation signal (e.g., activating mutations in RAS family genes or mutations/translocations leading to kinase pathway signaling). Genomic alterations leading to blockage of B-cell development include translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions), point mutations (e.g., IKZF1 and PAX5), and intragenic/intergenic deletions (e.g., IKZF1, PAX5, EBF, and ERG).[
The genomic alterations in B-ALL tend not to occur at random, but rather to cluster within subtypes that can be delineated by biological characteristics such as their gene expression profiles. Cases with recurring chromosomal translocations (e.g., TCF3::PBX1 and ETV6::RUNX1 fusions and KMT2A-rearranged ALL) have distinctive biological features and illustrate this point, as do the examples below of specific genomic alterations within unique biological subtypes:
Activating point mutations in kinase genes are uncommon in high-risk B-ALL. JAK genes are the primary kinases that are found to be mutated. These mutations are generally observed in patients with BCR::ABL1-like ALL that have CRLF2 abnormalities, although JAK2 mutations are also observed in approximately 15% of children with Down syndrome and ALL.[
Understanding of the genomics of B-ALL at relapse is less advanced than the 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.[
A number of recurrent chromosomal abnormalities have been shown to have prognostic significance, especially in B-ALL. Some chromosomal alterations are associated with more favorable outcomes, such as favorable trisomies (51–65 chromosomes) and the ETV6::RUNX1 fusion.[
In recognition of the clinical significance of many of these genomic alterations, the 5th edition revision of the World Health Organization Classification of Haematolymphoid Tumours lists the following entities for B-ALL:[
The category of B-ALL with other defined genetic abnormalities includes potential novel entities, including B-ALL with DUX4, MEF2D, ZNF384 or NUTM1 rearrangements; B-ALL with IG::MYC fusions; and B-ALL with PAX5alt or PAX5 p.P80R (NP_057953.1) abnormalities.
These and other chromosomal and genomic abnormalities for childhood ALL are described below.
High hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in approximately 33% of NCI standard-risk and 14% of NCI high-risk pediatric B-ALL cases.[
High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is an independent favorable prognostic factor.[
While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[
Multiple reports have described the prognostic significance of specific chromosome trisomies among children with hyperdiploid B-ALL.
Chromosomal translocations may be seen with high hyperdiploidy, and in those cases, patients are more appropriately risk-classified on the basis of the prognostic significance of the translocation. For instance, in one study, 8% of patients with the BCR::ABL1 fusion also had high hyperdiploidy,[
Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[
Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[
The genomic landscape of hyperdiploid ALL is characterized by mutations in genes of the receptor tyrosine kinase (RTK)/RAS pathway in approximately one-half of cases. Genes encoding histone modifiers are also present in a recurring manner in a minority of cases. Analysis of mutation profiles demonstrates that chromosomal gains are early events in the pathogenesis of hyperdiploid ALL and may occur in utero, while mutations in RTK/RAS pathway genes are late events in leukemogenesis and are often subclonal.[
B-ALL cases with fewer than the normal number of chromosomes have been subdivided in various ways, with one report stratifying on the basis of modal chromosome number into the following four groups:[
Near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.[
Low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.[
Most patients with hypodiploidy are in the near-haploid and low-hypodiploid groups, and both of these groups have an elevated risk of treatment failure compared with nonhypodiploid cases.[
The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[
Fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in approximately 27% of NCI standard-risk and 10% of NCI high-risk pediatric B-ALL cases.[
The ETV6::RUNX1 fusion produces a cryptic translocation that is detected by methods such as FISH, rather than conventional cytogenetics, and it occurs most commonly in children aged 2 to 9 years.[
Reports generally indicate favorable EFS and overall survival (OS) rates in children with the ETV6::RUNX1 fusion; however, the prognostic impact of this genetic feature is modified by the following factors:[
In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6::RUNX1 fusion status, to be independent prognostic factors.[
There is a higher frequency of late relapses in patients with ETV6::RUNX1 fusions compared with other relapsed B-ALL patients.[
The BCR::ABL1 fusion leads to production of a BCR::ABL1 fusion protein with tyrosine kinase activity (see Figure 3).[
Figure 3. The Philadelphia chromosome is a translocation between the ABL1 oncogene (on the long arm of chromosome 9) and the BCR gene (on the long arm of chromosome 22), resulting in the fusion gene BCR::ABL1. BCR::ABL1 encodes an oncogenic protein with tyrosine kinase activity.
This subtype of ALL is more common in older children with B-ALL and high WBC counts, with the incidence of the BCR::ABL1 fusions increasing to about 25% in young adults with ALL.
Historically, the BCR::ABL1 fusion was associated with an extremely poor prognosis (especially in those who presented with a high WBC count or had a slow early response to initial therapy), and its presence had been considered an indication for allogeneic hematopoietic stem cell transplantation (HSCT) in patients in first remission.[
Rearrangements involving the KMT2A gene with more than 100 translocation partner genes result in the production of fusion oncoproteins. KMT2A gene rearrangements occur in up to 80% of infants with ALL. Beyond infancy, approximately 1% of NCI standard-risk and 4% of NCI high-risk pediatric B-ALL cases have KMT2A rearrangements.[
These rearrangements are generally associated with an increased risk of treatment failure.[
Patients with KMT2A::AFF1 fusions are usually infants with high WBC counts. These patients are more likely than other children with ALL to have central nervous system (CNS) disease and to have a poor response to initial therapy.[
Whole-genome sequencing has determined that cases of infant ALL with KMT2A gene rearrangements have few additional genomic alterations, none of which have clear clinical significance.[
Of interest, the KMT2A::MLLT1 fusion (t(11;19)(q23;p13.3)) occurs in approximately 1% of ALL cases and occurs in both early B-lineage ALL and T-ALL.[
Fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1 is present in approximately 4% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[
The TCF3::PBX1 fusion had been associated with inferior outcome in the context of antimetabolite-based therapy,[
The TCF3::HLF fusion occurs in less than 1% of pediatric ALL cases. ALL with the TCF3::HLF fusion is associated with disseminated intravascular coagulation and hypercalcemia at diagnosis. Outcome is very poor for children with the TCF3::HLF fusion, with a literature review noting mortality for 20 of 21 cases reported.[
Approximately 3% of NCI standard-risk and 6% of NCI high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.[
ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%. Even when the IZKF1 deletion is present, prognosis remains highly favorable.[
Gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 0.3% of NCI standard-risk and 3% of NCI high-risk pediatric B-ALL cases.[
Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[
The median age at diagnosis for cases of MEF2D-rearranged ALL in studies that included both adult and pediatric patients was 12 to 14 years.[
ZNF384 is a transcription factor that is rearranged in approximately 0.3% of NCI standard-risk and 2.7% of NCI high-risk pediatric B-ALL cases.[
East Asian ancestry was associated with an increased prevalence of ZNF384.[
NUTM1-rearranged B-ALL is most commonly observed in infants, representing 3% to 5% of overall cases of B-ALL in this age group and approximately 20% of infant B-ALL cases lacking the KMT2A rearrangement.[
The NUTM1 gene is located on chromosome 15q14, and some cases of B-ALL with NUTM1 rearrangements show chromosome 15q aberrations, but other cases are cryptic and have no cytogenetic abnormalities.[
The NUTM1 rearrangement appears to be associated with a favorable outcome.[
This entity is included in the 2016 revision of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.[
The number of cases of IGH::IL3 ALL described in the published literature is too small to assess the prognostic significance of the IGH::IL3 fusion. Diagnosis of cases of IGH::IL3 ALL may be delayed because the ALL clone in the bone marrow may be small, and because it can present with hypereosinophilia in the absence of cytopenias and circulating blasts.[
iAMP21 is generally diagnosed using FISH and is defined by the presence of greater than or equal to five RUNX1 signals per cell (or ≥3 extra copies of RUNX1 on a single abnormal chromosome).[
iAMP21 is associated with older age (median, approximately 10 years), presenting WBC count of less than 50 × 109 /L, a slight female preponderance, and high end-induction MRD.[
The United Kingdom Acute Lymphoblastic Leukaemia (UKALL) clinical trials group initially reported that the presence of iAMP21 conferred a poor prognosis in patients treated in the MRC ALL 97/99 trial (5-year EFS rate, 29%).[
Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, called PAX5alt and PAX5 p.P80R (NP_057953.1).[
PAX5alt. PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.[
Intragenic amplification of PAX5 was identified in approximately 1% of B-ALL cases, and it was usually detected in cases lacking known leukemia-driver genomic alterations.[
PAX5 p.P80R (NP_057953.1). PAX5 with a p.P80R mutation shows a gene expression profile distinctive from that of other cases with PAX5 alterations.[
Outcome for the pediatric patients with PAX5 p.P80R and PAX5alt treated in a COG clinical trial appears to be intermediate (5-year EFS rate, approximately 75%).[
BCR::ABL1-negative patients with a gene expression profile similar to BCR::ABL1-positive patients have been referred to as Ph-like,[
Retrospective analyses have indicated that patients with BCR::ABL1-like ALL have a poor prognosis.[
The hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations [
Many of the remaining cases of BCR::ABL1-like ALL have been noted to have a series of translocations involving tyrosine-kinase encoding ABL-class fusion genes, including ABL1, ABL2, CSF1R, and PDGFRB.[
BCR::ABL1-like ALL cases with non-CRLF2 genomic alterations represent approximately 3% of NCI standard-risk and 8% of NCI high-risk pediatric B-ALL cases.[
Approximately 9% of BCR::ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[
CRLF2. Genomic alterations in CRLF2, a cytokine receptor gene located on the pseudoautosomal regions of the sex chromosomes, have been identified in 5% to 10% of cases of B-ALL. These alterations represent approximately 50% of cases of BCR::ABL1-like ALL.[
BCR::ABL1-like B-ALL with CRLF2 genomic alterations is observed in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[
ALL with genomic alterations in CRLF2 occurs at a higher incidence in children with Hispanic or Latino genetic ancestry [
The P2RY8::CRLF2 fusion is observed in 70% to 75% of pediatric patients with CRLF2 genomic alterations, and it occurs in younger patients (median age, approximately 4 years vs. 14 years for patients with IGH::CRLF2).[
IGH::CRLF2 and P2RY8::CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[
CRLF2 abnormalities are strongly associated with the presence of IKZF1 deletions. Deletions of IKZF1 are more common in cases with IGH::CRLF2 fusions than in cases with P2RY8::CRLF2 fusions.[
Although the results of several retrospective studies suggest that CRLF2 abnormalities may have adverse prognostic significance in univariate analyses, most do not find this abnormality to be an independent predictor of outcome.[
IKZF1 deletions, including deletions of the entire gene and deletions of specific exons, are present in approximately 15% of B-ALL cases. Less commonly, IKZF1 can be inactivated by deleterious point mutations.[
Cases with IKZF1 deletions tend to occur in older children, have a higher WBC count at diagnosis, and are therefore more common in NCI high-risk patients than in NCI standard-risk patients.[
Multiple reports have documented the adverse prognostic significance of an IKZF1 deletion, and most studies have reported that this deletion is an independent predictor of poor outcome in multivariate analyses.[
There are few published results of changing therapy on the basis of IKZF1 gene status. The Malaysia-Singapore group published results of two consecutive trials. In the first trial (MS2003), IKZF1 status was not considered in risk stratification, while in the subsequent trial (MS2010), IKZF1-deleted patients were excluded from the standard-risk group. Thus, more IKZF1-deleted patients in the MS2010 trial received intensified therapy. Patients with IKZF1-deleted ALL had improved outcomes in MS2010 compared with patients in MS2003, but interpretation of this observation is limited by other changes in risk stratification and therapeutic differences between the two trials.[
MYC gene rearrangements are a rare but recurrent finding in pediatric patients with B-ALL. Patients with rearrangements of the MYC gene and the IGH2, IGK, and IGL genes at 14q32, 2p12, and 22q11.2, respectively, have been reported.[
T-ALL is characterized by genomic alterations leading to activation of transcriptional programs related to T-cell development and by a high frequency of cases (approximately 60%) with mutations in NOTCH1 and/or FBXW7 that result in activation of the NOTCH1 pathway.[
In Figure 4 below, pediatric T-ALL cases are divided into 10 molecular subtypes based on their RNA expression and gene mutation status. These cases were derived from patients enrolled in SJCRH and COG clinical trials.[
Figure 4. Genomic subtypes of T-ALL. The figure represents data from 466 children, adolescents, and young adults diagnosed with T-ALL and enrolled in St. Jude Children's Research Hospital or Children's Oncology Group clinical trials. Adapted from Brady SW, Roberts KG, Gu Z, et al.: The genomic landscape of pediatric acute lymphoblastic leukemia. Nature Genetics 54: 1376-1389, 2022.
Notch pathway signaling is commonly activated by NOTCH1 and FBXW7 gene mutations in T-ALL, and these are the most commonly mutated genes in pediatric T-ALL.[
The prognostic significance of NOTCH1 and FBXW7 mutations may be modulated by genomic alterations in RAS and PTEN. The French Acute Lymphoblastic Leukaemia Study Group (FRALLE) and the Group for Research on Adult Acute Lymphoblastic Leukemia reported that patients having mutated NOTCH1 or FBXW7 and wild-type PTEN and RAS constituted a favorable-risk group (i.e., low-risk group), while patients with PTEN or RAS mutations, regardless of NOTCH1 and FBXW7 status, have a significantly higher risk of treatment failure (i.e., high-risk group).[
Multiple chromosomal translocations have been identified in T-ALL that lead to deregulated expression of the target genes. These chromosome rearrangements fuse genes encoding transcription factors (e.g., TAL1, TAL2, LMO1, LMO2, LYL1, TLX1, TLX3, NKX2-I, HOXA, and MYB) to one of the T-cell receptor loci (or to other genes) and result in deregulated expression of these transcription factors in leukemia cells.[
Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[
Early T-cell precursor ALL cytogenetics/genomics
Detailed molecular characterization of early T-cell precursor ALL showed this entity to be highly heterogeneous at the molecular level, with no single gene affected by mutation or copy number alteration in more than one-third of cases.[
Studies have found that the absence of biallelic deletion of the TCR-gamma locus (ABD), as detected by comparative genomic hybridization and/or quantitative DNA-PCR, was associated with early treatment failure in patients with T-ALL.[
Mixed phenotype acute leukemia (MPAL) cytogenetics/genomics
For acute leukemias of ambiguous lineage, the WHO classification system is summarized in Table 1.[
|MPAL = mixed phenotype acute leukemia; NOS = not otherwise specified.|
| a Adapted from Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[
|Acute undifferentiated leukemia||Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage|
|MPAL withBCR::ABL1(t(9;22)(q34;q11.2))||Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have the (9;22) translocation or theBCR::ABL1rearrangement|
|MPAL withKMT2A(t(v;11q23))||Acute leukemia meeting the diagnostic criteria for MPAL in which the blasts also have a translocation involving theKMT2Agene|
|MPAL, B/myeloid, NOS (B/M MPAL)||Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR::ABL1orKMT2A|
|MPAL, T/myeloid, NOS (T/M MPAL)||Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involvingBCR::ABL1orKMT2A|
|MPAL, B/myeloid, NOS—rare types||Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage|
|Other ambiguous lineage leukemias||Natural killer–cell lymphoblastic leukemia/lymphoma|
| a Adapted from Arber et al.[
|b Strong defined as equal to or brighter than the normal B or T cells in the sample.|
|Myeloid lineage||Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry);or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)|
|T lineage||Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain);or surface CD3|
|B lineage||Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10;or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10|
The classification system for MPAL includes two entities that are defined by their primary molecular alteration: MPAL with BCR::ABL1 translocation and MPAL with KMT2A rearrangement. The genomic alterations associated with the MPAL, B/myeloid, NOS (B/M MPAL) and MPAL, T/myeloid, NOS (T/M MPAL) entities are distinctive, as described below:
Gene polymorphisms in drug metabolic pathways
A number of polymorphisms of genes involved in the metabolism of chemotherapeutic agents have been reported to have prognostic significance in childhood ALL.[
Patients with mutant phenotypes of TPMT (a gene involved in the metabolism of thiopurines such as mercaptopurine) appear to have more favorable outcomes,[
Germline variants in NUDT15 that reduce or abolish activity of this enzyme also lead to diminished tolerance to thiopurines.[
Gene polymorphisms may also affect the expression of proteins that play central roles in the cellular effects of anticancer drugs. As an example, patients who are homozygous for a polymorphism in the promoter region of CEP72 (a centrosomal protein involved in microtubule formation) are at increased risk of vincristine neurotoxicity.[
Genome-wide polymorphism analysis has identified specific single nucleotide polymorphisms associated with high end-induction MRD and risk of relapse. Polymorphisms of interleukin-15, as well as genes associated with the metabolism of etoposide and methotrexate, were significantly associated with treatment response in two large cohorts of ALL patients treated on SJCRH and COG protocols.[
For information about the treatment of childhood ALL, see Childhood Acute Lymphoblastic Leukemia Treatment.
Acute Myeloid Leukemia (AML)
Molecular features of acute myeloid leukemia
Comprehensive molecular profiling of pediatric and adult AML has shown that AML is a disease demonstrating both commonalities and differences across the age spectrum.[
Genetic analysis of leukemia blast cells (using both conventional cytogenetic methods and molecular methods) is performed on children with AML because both chromosomal and molecular abnormalities are important diagnostic and prognostic markers.[
Detection of molecular abnormalities can also aid in risk stratification and treatment allocation. For example, mutations of NPM and CEBPA are associated with favorable outcomes while certain mutations of FLT3 portend a high risk of relapse, and identifying the latter mutations may allow for targeted therapy.[
The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia emphasizes that recurrent chromosomal translocations in pediatric AML may be unique or have a different prevalence than in adult AML.[
|Gene Fusion Product||Chromosomal Translocation||Prevalence in Pediatric AML (%)|
|a Cryptic chromosomal translocation.|
|CBFB-MYH11||inv(16)(p13.1;q22) or t(16;16)(p13.1;q22)||4–9|
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. In a study of 20 cases for which sequencing data were available at diagnosis and relapse, a key finding was that the variant allele frequency at diagnosis strongly correlated with persistence of mutations at relapse.[
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. The nomenclature of the 2016 revision to the WHO classification of myeloid neoplasms and acute leukemia is incorporated for disease entities where relevant.
Genetic abnormalities associated with a favorable prognosis
Genetic abnormalities associated with a favorable prognosis include the following:
Both RUNX1-RUNX1T1 and CBFB-MYH11 subtypes commonly show mutations in genes that activate receptor tyrosine kinase signaling (e.g., NRAS, FLT3, and KIT); NRAS and KIT are the most commonly mutated genes for both subtypes. The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.[
Although both RUNX1-RUNX1T1 and CBFB-MYH11 fusion genes disrupt the activity of CBF, cases with these genomic alterations have distinctive secondary mutations.[
A study of 204 adults with RUNX1-RUNX1T1 AML found that ASXL2 mutations (present in 17% of cases) and ASXL1 or ASXL2 mutations (present in 25% of cases) lacked prognostic significance.[
Utilization of quantitative reverse transcriptase–polymerase chain reaction (RT-PCR) for PML-RARA transcripts has become standard practice.[
Studies of children with AML suggest a lower rate of occurrence of NPM1 mutations in children compared with adults with normal cytogenetics. NPM1 mutations occur in approximately 8% of pediatric patients with AML and are uncommon in children younger than 2 years.[
CEBPA mutations occur in approximately 5% of children with AML and have been preferentially found in the cytogenetically normal subtype of AML with FAB M1 or M2.
GATA1 mutations confer increased sensitivity to cytarabine by down-regulating cytidine deaminase expression, possibly providing an explanation for the superior outcome of children with Down syndrome and M7 AML when treated with cytarabine-containing regimens.[
Genetic abnormalities associated with an unfavorable prognosis
Genetic abnormalities associated with an unfavorable prognosis include the following:
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.[
Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[
Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.
The prognostic significance of FLT3 ITD is modified by the presence of other recurring genomic alterations. The prevalence of FLT3 ITD is increased in certain genomic subtypes of pediatric AML, including those with the NUP98-NSD1 fusion gene, of which 80% to 90% have FLT3 ITD.[
For APL, FLT3 ITD and point mutations occur in 30% to 40% of children and adults.[
Activating point mutations of FLT3 have also been identified in both adults and children with AML, although the clinical significance of these mutations is not clearly defined. Some of these point mutations appear to be specific to pediatric patients.[
Other genetic abnormalities observed in pediatric AML
Other genetic abnormalities observed in pediatric AML include the following:
The most common translocation, representing approximately 50% of KMT2A-rearranged cases in the pediatric AML population, is t(9;11)(p22;q23), in which the KMT2A gene is fused with MLLT3 gene.[
The median age for 11q23/KMT2A-rearranged cases in children is approximately 2 years, and most translocation subgroups have a median age at presentation of younger than 5 years.[
Outcome for patients with de novo AML and KMT2A gene rearrangements is generally reported as being similar to or slightly worse than the outcome observed in other patients with AML.[
For patients with the most prevalent KMT2A-rearranged subtype of AML, t(9;11)(p21.3;q23.3)/MLLT3-KMT2A, single clinical trial groups have variably described a more favorable prognosis; however, neither the international retrospective study nor the COG study confirmed the favorable prognosis for this subgroup.[
KMT2A-rearranged AML subgroups that are associated with poor outcome include the following:
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.[
In a study of approximately 2,000 children with AML, the CBFA2T3-GLIS2 fusion was identified in 39 cases (1.9%), with a median age at presentation of 1.5 years, and with all cases observed in children younger than 3 years.[
An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS rate of 54.5% and an OS rate of 58.2%, similar to the rates for other children with AMKL.[
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.[
The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[
The NUP98-KDM5A fusion gene results from the fusion of the NUP98 gene with the KDM5A gene, which results from a cytogenetically cryptic translocation, t(11;12)(p15;p13).[
The prognostic significance of activating KIT mutations in adults with CBF AML has been studied with conflicting results. A meta-analysis found that KIT mutations appear to increase the risk of relapse without an impact on OS for adults with RUNX1-RUNX1T1 AML.[
In children with AML, WT1 mutations are observed in approximately 10% of cases.[
In a study of children with refractory AML, WT1 was overrepresented compared with a cohort who did achieve remission (54% [15 of 28 patients] vs. 15%).[
Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[
Activating mutations in CSF3R 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.[
For information about the treatment of childhood AML, see Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Juvenile Myelomonocytic Leukemia (JMML)
Molecular features of JMML
The genomic landscape of JMML is characterized by mutations in one of five genes of the RAS pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[
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.[
A report describing the genomic landscape of JMML found that 16 of 150 patients (11%) lacked canonical RAS pathway mutations. Among these 16 patients, 3 were observed to have in-frame fusions involving receptor tyrosine kinases (DCTN1-ALK, RANBP2-ALK, and TBL1XR1-ROS1). These patients all had monosomy 7 and were aged 56 months or older. One patient with an ALK fusion was treated with crizotinib plus conventional chemotherapy and achieved a complete molecular remission and proceeded to allogeneic bone marrow transplantation.[
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 : 1334-40, 2015), copyright (2015).
Prognosis (genomic and molecular factors)
Several genomic factors affect the prognosis of patients with JMML, including the following:
For information about the treatment of JMML, see Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Myelodysplastic Syndromes (MDS)
Molecular features of myelodysplastic syndromes (MDS)
Pediatric MDS are associated with a distinctive constellation of genetic alterations compared with MDS arising in adults. In adults, MDS often evolves from clonal hematopoiesis and is characterized by mutations in TET2, DNMT3A, and TP53. In contrast, mutations in these genes are rare in pediatric MDS, while mutations in GATA2, SAMD9/SAMD9L, SETBP1, ASXL1, and RAS/MAPK pathway genes are observed in subsets of pediatric MDS cases.[
A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric patients with primary MDS and targeted sequencing for another 14 cases.[
A second report described the application of a targeted sequencing panel of 105 genes to 50 pediatric patients with MDS (refractory cytopenia of childhood = 31 and MDS-EB = 19) and was enriched for cases with monosomy 7 (48%).[
Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[
SAMD9 and SAMD9L germline mutations are both associated with pediatric MDS cases in which there is an additional loss of all or part of chromosome 7.[
For information about the treatment of childhood MDS, see Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
Mature B-cell Lymphoma
The mature B-cell lymphomas include Burkitt lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.
Genomics of Burkitt lymphoma/leukemia
The malignant cells of Burkitt lymphoma/leukemia show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin (Ig), most bearing a clonal surface IgM 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 lymphomas/leukemias express 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 MYC oncogene and the immunoglobulin locus (IG, mostly the IGH locus) regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[
Mapping of IGH-translocation breakpoints demonstrated that IG::MYC translocations in sporadic Burkitt lymphoma most commonly occur through aberrant class-switch recombination and less commonly through somatic hypermutation. Translocations resulting from aberrant variable, diversity, and joining (VDJ) gene segment recombinations are rare.[
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Some of the more commonly observed recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases. However, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, CCND3, TP53, and apoptosis.[
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater.[
Genomics of Burkitt-like lymphoma with 11q aberration
Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues.[
For information about the treatment of childhood Burkitt lymphoma/leukemia, see Childhood Non-Hodgkin Lymphoma Treatment.
Diffuse large B-cell lymphoma
Genomics of diffuse large B-cell lymphoma
The World Health Organization (WHO) classification system categorizes diffuse large B-cell lymphoma on the basis of molecular characteristics into the germinal center B-cell subtype and the activated B-cell subtype, with the remaining types being classified as diffuse large B-cell lymphoma, not otherwise specified (NOS).[
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
Large B-cell lymphoma with IRF4 rearrangement (LBCL-IRF4) was added as a provisional entity in the 2017 revision of the WHO classification of lymphoid neoplasms.[
High-grade B-cell lymphoma, NOS is defined as a clinically aggressive B-cell lymphoma that lacks MYC plus BCL2 and/or BCL6 rearrangements and that does not meet criteria for diffuse large B-cell lymphoma, NOS or Burkitt lymphoma.[
For information about the treatment of childhood diffuse large B-cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.
Primary mediastinal B-cell lymphoma
Genomics of 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.[
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
Primary mediastinal B-cell lymphoma has distinctive gene expression and mutation profiles compared with diffuse large B-cell lymphoma. However, its gene expression and mutation profiles have features similar to those seen in Hodgkin lymphoma.[
For information about the treatment of childhood primary mediastinal B-cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.
Genomics of lymphoblastic lymphoma
Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% of cases having a T-cell immunophenotype and the remaining cases having a precursor B-cell phenotype.[
As opposed to pediatric T-cell acute lymphoblastic leukemia (T-ALL), chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not as well characterized. Many genomic alterations that occur in T-ALL also occur in T-cell lymphoblastic lymphoma. Examples include the following:
For the genomic alterations described above, NOTCH1 and FBXW7 mutations may confer a more favorable prognosis for patients with T-cell lymphoblastic lymphoma, while loss of heterozygosity at chromosome 6q, PTEN mutations, and KMT2D mutations may be associated with an inferior prognosis.[
There have been few studies of the genomic characteristics of B-lymphoblastic lymphoma. A report describing copy number alterations for pediatric B-lymphoblastic lymphoma cases noted that some gene deletions that are common in B-ALL (e.g., CDKN2A, IKZF1, and PAX5) appeared to occur with appreciable frequency in B-lymphoblastic lymphoma.[
For information about the treatment of childhood lymphoblastic lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.
Anaplastic Large Cell Lymphoma
Genomics of 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 ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM::ALK. The other 15% of cases are composed of variant ALK translocations.[
|Gene Fusion||Partner Chromosome Location||Frequency of Gene Fusion|
| a Adapted from Tsuyama et al.[
In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior.[
In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002).[
For information about the treatment of childhood anaplastic large cell lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.
Pediatric-type Follicular Lymphoma
Genomics of pediatric-type follicular lymphoma
Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 and IRF4 rearrangements, resulting in IRF4/MUM1 expression. BCL6 and MYC rearrangements are also not present.[
For information about the treatment of pediatric-type follicular lymphoma, see Childhood Non-Hodgkin Lymphoma Treatment.
Genomics of Classical Hodgkin Lymphoma
Classical Hodgkin lymphoma has a gene expression and mutation profile that differs from that of other lymphomas. The exception is primary mediastinal B-cell lymphoma, which shares many genomic and cytogenetic characteristics with Hodgkin lymphoma.[
The genomic alterations observed in Hodgkin lymphoma fall into several categories, including immune evasion alterations, JAK-STAT pathway alterations, alterations leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) activation, and others:
Genomics of Nodular Lymphocyte-Predominant Hodgkin Lymphoma
The lymphocyte-predominant (LP) cells of nodular lymphocyte-predominant Hodgkin lymphoma have distinctive genomic characteristics compared with the HRS cells of Hodgkin lymphoma. As with Hodgkin lymphoma, genomic characterization is complicated by the low percentage of malignant cells within a tumor mass.
For information about the treatment of childhood Hodgkin lymphoma, see Childhood Hodgkin Lymphoma Treatment.
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.[
Pilocytic Astrocytomas and Other Astrocytic Tumors
Molecular features of low-grade gliomas
Pilocytic and diffuse astrocytomas
Genomic alterations involving activation of BRAF and the ERK/MAPK pathway are very common in sporadic cases of pilocytic astrocytoma, a type of low-grade glioma.
BRAF activation in pilocytic astrocytoma occurs most commonly through a BRAF-KIAA1549 gene fusion, producing a fusion protein that lacks the BRAF regulatory domain.[
Presence of the BRAF-KIAA1549 fusion predicted a better clinical outcome (progression-free survival [PFS] and overall survival [OS]) in one report that described children with incompletely resected low-grade gliomas.[
BRAF activation through the BRAF-KIAA1549 fusion has also been described in other pediatric low-grade gliomas (e.g., pilomyxoid astrocytoma).[
BRAF V600E point mutations are occasionally observed in pilocytic astrocytoma; the mutations are also observed in nonpilocytic pediatric low-grade gliomas, including ganglioglioma,[
Studies have observed the following:
Activating mutations in FGFR1, PTPN11, and NTRK2 fusion genes have also been identified in noncerebellar pilocytic astrocytomas.[
Angiocentric gliomas typically arise in children and young adults as cerebral tumors presenting with seizures.[
Two reports in 2016 identified MYB gene alterations as being present in almost all cases diagnosed as angiocentric glioma, with QKI being the primary fusion partner in cases where fusion-partner testing was possible.[
Astroblastomas are defined histologically as glial neoplasms composed of GFAP-positive cells and contain astroblastic pseudorosettes that often demonstrate sclerosis. Astroblastomas are diagnosed primarily in childhood through young adulthood.[
The following studies have described genomic alterations associated with astroblastoma:
These reports suggest that the histologic diagnosis of astroblastoma encompasses a heterogeneous group of genomically defined entities; astroblastomas with MN1 fusions represent a distinctive subset of histologically diagnosed cases.[
Neurofibromatosis type 1 (NF1)
Children with NF1-associated low-grade gliomas often have tumors in the optic pathway that are not biopsied. In a series of pediatric patients (n = 17; median age, 10 years) with NF1-associated low-grade gliomas in which tissue was collected and subjected to whole-exome sequencing, the number of mutations was very low (median, 6 per case).[
Most children with tuberous sclerosis have a germline mutation in one of two tuberous sclerosis genes (TSC1 or TSC2). 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.[
For information about the treatment of low-grade childhood astrocytomas, see Childhood Astrocytomas Treatment.
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, H3 K27M-mutant (grade IV]).
For pediatric diffuse astrocytomas (grade II), rearrangements in the MYB family of transcription factors (MYB and MYBL1) are the most commonly reported genomic alteration.[
Anaplastic astrocytomas and glioblastomas
Molecular features of high-grade gliomas
Pediatric high-grade gliomas, especially glioblastoma multiforme, are biologically distinct from those arising in adults.[
Subgroups identified using DNA methylation patterns
Pediatric high-grade gliomas can be separated into distinct subgroups on the basis of epigenetic patterns (DNA methylation), and these subgroups show distinguishing chromosome copy number gains/losses and gene mutations in the tumor.[
The following pediatric high-grade glioma subgroups were identified on the basis of their DNA methylation patterns, and they show distinctive molecular and clinical characteristics:[
Patients with H3F3A mutations are at high risk of treatment failure,[
Pediatric glioblastoma multiforme high-grade glioma patients whose tumors lack both histone mutations and IDH1 mutations represent approximately 40% of pediatric glioblastoma multiforme cases.[
High-grade gliomas in infants
Infants and young children with high-grade gliomas appear to have tumors with distinctive molecular characteristics when compared with tumors of older children and adults with high-grade gliomas. An indication of this difference was noted with the application of DNA methylation analysis to pediatric high-grade tumors, which found that approximately 7% of pediatric patients with a histological diagnosis of high-grade glioma had tumors with methylation patterns more closely resembling those of low-grade gliomas.[
Two studies of the molecular characteristics of high-grade gliomas in infants and young children have further defined the distinctive nature of tumors arising in children younger than 1 year. A key finding from both studies is the importance of gene fusions involving tyrosine kinases (e.g., ALK, NTRK1, NTRK2, NTRK3, and ROS1) in patients in this age group. Both studies also found that infants with high-grade gliomas whose tumors have these gene fusions have survival rates much higher than those of older children with high-grade gliomas.[
The first study presented data for 118 children younger than 1 year with a low-grade or high-grade glioma diagnosis who had tumor tissue available for genomic characterization.[
The second study focused on tumors from children younger than 4 years with a pathological diagnosis of WHO grades II, III, and IV gliomas, astrocytomas, or glioneuronal tumors. Among the 191 tumors studied that met inclusion criteria, 61 had methylation profiles consistent with glioma subtypes that occur in older children (e.g., IDH1, diffuse midline glioma K27M-mutant, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, etc.). The remaining 130 cases were termed the intrinsic set and were the focus of additional molecular characterization:[
Secondary high-grade glioma
Childhood secondary high-grade glioma (high-grade glioma that is preceded by a low-grade glioma) is uncommon (2.9% in a study of 886 patients). No pediatric low-grade gliomas with the BRAF-KIAA1549 fusion transformed to a high-grade glioma, whereas low-grade gliomas with the BRAF V600E mutations were associated with increased risk of transformation. Seven of 18 patients (approximately 40%) with secondary high-grade glioma had BRAF V600E mutations, with CDKN2A alterations present in 8 of 14 cases (57%).[
Neurofibromatosis type 1 (NF1)
High-grade gliomas can arise in children with NF1, although low-grade gliomas are much more common. When a high-grade tumor occurs, it is most often in adulthood. Genomic characterization of 23 patients with NF1-associated high-grade gliomas (median age, 38.8 years; 5 patients younger than 18 years) showed higher rates of mutations compared with NF1 patients who had low-grade gliomas (21.5 vs. 6 mutations, respectively).[
For information about the treatment of high-grade childhood astrocytomas, see Childhood Astrocytomas Treatment.
Neuronal and Mixed Neuronal-Glial Tumors
Molecular features of neuronal and mixed neuronal-glial tumors
Neuronal and mixed neuronal-glial tumors are generally low-grade tumors, with an exception of the grade III anaplastic gangliogliomas. The histologies recognized by the 2016 WHO classification include the following:[
Dysembryoplastic neuroepithelial tumor (DNET)
DNET presents in children and adults, with the median age at diagnosis in mid-to-late adolescence. It is characterized histopathologically by the presence of columns of oligodendroglial-like cells and cortical ganglion cells floating in mucin.[
FGFR1 alterations have been reported in 60% to 80% of DNETs, and include FGFR1 activating point mutations, internal tandem duplication of the kinase domain, and activating gene fusions.[
DNET of the septum pellucidum
Septal DNET generally presents with symptoms related to obstructive hydrocephalus.[
Mutations that are common in low-grade gliomas (e.g., BRAF V600E) and in cortical DNETs (FGFR1 mutations) are uncommon in septal DNET.[
A report of the molecular characterization of 18 septal DNETs showed that 14 had a PDGFRA mutation, with all but one being a mutation at the K385 residue,[
Ganglioglioma presents during childhood and into adulthood. It most commonly arises in the cerebral cortex and is associated with seizures, but also presents in other sites, including the spinal cord.[
The unifying theme for the molecular pathogenesis of ganglioglioma is genomic alterations leading to MAPK pathway activation.[
Desmoplastic infantile astrocytomas (DIA) and desmoplastic infantile gangliogliomas (DIG)
DIA and DIG most often present in the first year of life and show a characteristic imaging appearance in which a contrast-enhancing solid nodule accompanies a large cystic component.[
The most commonly observed genomic alterations in DIA and DIG are BRAF mutations involving V600; gene fusions involving kinase genes are observed less frequently.
Papillary glioneuronal tumor
Papillary glioneuronal tumor is a low-grade biphasic neoplasm with astrocytic and neuronal differentiation that primarily arises in the supratentorial compartment.[
The primary genomic alteration associated with papillary glioneuronal tumor is a gene fusion, SLC44A1-PRKCA, that is associated with the t(9:17)(q31;q24) translocation.[
Rosette-forming glioneuronal tumor (RGNT)
RGNT presents in adolescents and adults, with tumors generally located infratentorially, although tumors can arise in mesencephalic or diencephalic regions.[
DNA methylation profiling shows that RGNT has a distinct epigenetic profile that distinguishes it from other low-grade glial/glioneuronal tumor entities.[
Diffuse leptomeningeal glioneuronal tumor (DLGNT)
DLGNT is a rare CNS tumor that has been characterized radiographically by leptomeningeal enhancement on magnetic resonance imaging (MRI) that may involve the posterior fossa, brain stem region, and spinal cord.[
DLGNT showed a distinctive epigenetic profile on DNA methylation arrays, and unsupervised clustering of array data applied to 30 cases defined two subclasses of DLGNT: methylation class (MC)-1 (n = 17) and MC-2 (n = 13).[
Extraventricular neurocytoma is histologically similar to central neurocytoma, consisting of small uniform cells that demonstrate neuronal differentiation, but it arises in the brain parenchyma rather than in association with the ventricular system.[
In a study of 40 tumors histologically classified as extraventricular neurocytoma and subjected to methylation array analysis, only 26 formed a separate cluster distinctive from reference tumors of other histologies.[
Diffuse Midline Glioma, H3 K27M-Mutant (Including Diffuse Intrinsic Pontine Gliomas [DIPGs])
The diffuse midline glioma, H3 K27M-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 H3 K27M mutation arising in midline structures such as the thalamus.
Genomics of DIPGs
The genomic characteristics of DIPGs appear to differ from those of many other pediatric high-grade gliomas of the cerebrum and from those of adult high-grade gliomas.[
In one report of 64 children with thalamic tumors, 50% of high-grade gliomas (11 of 22) had an H3 K27M mutation, and approximately 10% of tumors with low-grade morphological characteristics (5 of 42) had an H3 K27M mutation. Five-year overall survival (OS) was only 6% (1 of 16).[
A number of chromosomal and genomic abnormalities have been reported for DIPG, including the following:
An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that the H3 K27M mutation was invariably present, supporting its role as a driver mutation for DIPG.[
Patients with H3.1 K27M mutations have a longer median survival (15 months) than do patients with H3.3 K27M mutations (10.4 months).[
An autopsy study that examined multiple tumor sites (primary, contiguous, and metastatic) in seven DIPG patients found that PDGFRA amplification was variably present across these sites, suggesting that this change is a secondary genomic alteration in DIPG.[
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.[
(Refer to the Genomic Alterations section in the PDQ summary on Childhood Astrocytomas Treatment for more information about the genetics of low-grade gliomas.)
For information about the treatment of childhood brain stem gliomas, see Childhood Brain Stem Glioma Treatment.
Central Nervous System (CNS) Atypical Teratoid/Rhabdoid Tumors (AT/RT)
AT/RT was the first primary pediatric brain tumor in which a candidate tumor suppressor gene, SMARCB1 (previously known as INI1 and hSNF5), was identified.[
Rare cases of rhabdoid tumors expressing SMARCB1 and lacking SMARCB1 mutations have also been associated with somatic or germline mutations of SMARCA4/BRG1, another member of the SWI/SNF chromatin-remodeling complex.[
Less commonly, SMARCA4-negative (with retained SMARCB1) tumors have been described.[
The 2016 WHO classification defines AT/RT by the presence of either SMARCB1 or SMARCA4 alterations. Tumors with histological features of AT/RT that lack these genomic alterations are termed CNS embryonal tumor with rhabdoid features.[
Despite the absence of recurring genomic alterations beyond SMARCB1 and SMARCA4,[
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.[
In addition to somatic mutations, germline mutations in SMARCB1 have been reported in a substantial subset of patients with AT/RT.[
Gonadal mosaicism has also been observed, as evidenced by families in which multiple siblings are affected by AT/RT and have identical SMARCB1 alterations, but both parents lack a SMARCB1 mutation/deletion.[
Loss of SMARCB1 or SMARCA4 protein expression has therapeutic significance, because this loss creates a dependence of the cancer cells on EZH2 activity.[
For information about the treatment of childhood CNS AT/RTs, see Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors Treatment.
Molecular subtypes of medulloblastoma
Multiple medulloblastoma subtypes have been identified by integrative molecular analysis.[
Different regions of the same tumor are likely to have other disparate genetic mutations, adding to the complexity of devising effective molecularly targeted therapy.[
Further subclassification within these subgroups is possible, which will provide even more prognostic information.[
WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[
CTNNB1 mutations are observed in 85% to 90% of WNT medulloblastoma cases, with APC mutations detected in many of the cases that lack CTNNB1 mutations. Patients with WNT medulloblastoma whose tumors have APC mutations often have Turcot syndrome (i.e., germline APC mutations).[
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.[
Medulloblastoma, SHH-activated andTP53-mutant and medulloblastoma, SHH-activated andTP53-wild type
SHH tumors are medulloblastomas with aberrations in the SHH pathway and represent approximately 25% of medulloblastoma cases.[
Heterozygous deleterious germline mutations in the GPR161 gene were identified in approximately 3% of cases of SHH medulloblastoma.[
Mutations in the third nucleotide (r.3A>G) of the U1 spliceosomal small nuclear RNAs (snRNAs) are highly specific for SHH medulloblastoma.[
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. The heterogeneity in age at presentation maps to distinctive subsets identified by further molecular characterization, as follows:
Reports that used DNA methylation arrays have also identified two subtypes of SHH medulloblastoma in young children.[
The outcome for patients with nonmetastatic SHH medulloblastoma is relatively favorable for children younger than 3 years and for adults.[
Patients with unfavorable molecular findings have an unfavorable prognosis, with fewer than 50% of patients surviving after conventional treatment.[
The 2021 WHO classification identifies SHH medulloblastoma with a TP53 mutation as a distinctive entity (medulloblastoma, SHH-activated and TP53-mutant).[
The WHO classification combines group 3 and group 4 medulloblastoma cases into a single entity, partly on the basis of the absence of immediate clinical impact for this distinction. Group 3 medulloblastoma represents approximately 25% of medulloblastoma cases, while group 4 medulloblastoma represents approximately 40% of medulloblastoma cases.[
Various genomic alterations are observed in group 3 and group 4 medulloblastomas; however, no single alteration occurs in more than 10% to 20% of cases. Genomic alterations include the following:
Group 3 patients with MYC amplification or MYC overexpression have a poor prognosis.[
Group 4 medulloblastomas occur throughout infancy and childhood and into adulthood. The prognosis for group 4 medulloblastoma patients is similar to that for patients with other non-WNT medulloblastomas and may be affected by additional factors such as the presence of metastatic disease, chromosome 11q loss, and chromosome 17p loss.[
For group 3 and group 4 standard-risk patients (i.e., without MYC amplification or metastatic disease), the gain or loss of whole chromosomes appears to connote a favorable prognosis. This finding was derived from the data of 91 patients with non-WNT/non-SHH medulloblastoma enrolled in the SIOP-PNET-4 (NCT01351870) clinical trial and was confirmed in an independent group of 70 children with non-WNT/non-SHH medulloblastoma treated between 1990 and 2014.[
The classification of medulloblastoma into the four major subtypes will likely be altered in the future.[
It is unknown whether the classification for adults with medulloblastoma has a predictive ability similar to that for children.[
For information about the treatment of childhood medulloblastoma, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.
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 primitive neuroectodermal tumors (PNET) from the diagnostic lexicon.[
Molecular subtypes of nonmedulloblastoma embryonal tumors
Studies applying unsupervised clustering of DNA methylation patterns for 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).[
Among the tumors diagnosed as nonmedulloblastoma embryonal tumors, molecular characterization identified genomically and biologically distinctive subtypes, including the following:
ETMRs are defined at the molecular level by high-level amplification of the microRNA cluster C19MC and by a gene fusion between TTYH1 and C19MC.[
Although not listed as separate entities in the 2021 WHO Classification of Tumours of the CNS, other nonmedulloblastoma embryonal tumors occur relatively often or are often discussed as separate entities, including the following:
For information about the treatment of childhood PNETs, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.
Genomics of Pineoblastoma
Pineoblastoma, which was previously conventionally grouped with embryonal tumors, is now categorized by the World Health Organization (WHO) as a pineal parenchymal tumor. Given that therapies for pineoblastoma are quite similar to those used for embryonal tumors, the previous convention of including pineoblastoma with the central nervous system (CNS) embryonal tumors is followed here. Pineoblastoma is associated with germline mutations in both the RB1 gene and in DICER1, as described below:
For information about the treatment of childhood pineoblastoma, see Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment.
Molecular Subgroups of Ependymoma
Molecular characterization studies have previously identified nine molecular subgroups of ependymoma, six of which predominate in childhood. The subgroups are determined by their distinctive DNA methylation and gene expression profiles and unique spectrum of genomic alterations (see Figure 6).[
One new molecularly defined ependymoma was added to the 2021 World Health Organization (WHO) Classification of Tumours of the Central Nervous System: spinal ependymoma with MYCN amplification. The 2021 classification further described ependymal tumors defined by anatomical location and histology but not by molecular alteration. These tumors are called posterior fossa ependymoma (PF-EPN), supratentorial ependymoma (ST-EPN), and spinal ependymoma (SP-EPN). These tumors either contain a unique molecular alteration (not elsewhere classified [NEC]) or their molecular analysis failed or was not obtained (not otherwise specified [NOS]).[
Subependymoma—whether supratentorial, infratentorial, or spinal—accounts for the remaining three molecular variants, and it is rarely, if ever, seen in children.
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.
Posterior fossa A ependymoma (PF-EPN-A)
The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:
A study that included over 600 cases of PF-EPN-A used methylation array profiling to divide this population into two distinctive subgroups, PFA-1 and PFA-2.[
Posterior fossa B ependymoma (PF-EPN-B)
The PF-EPN-B subgroup is less common than the PF-EPN-A subgroup, representing 15% to 20% of all posterior fossa ependymomas in children. PF-EPN-B is characterized by the following:
Supratentorial ependymomas withZFTAfusions (ST-EPN-ZFTA)
ST-EPN-ZFTA is the largest subset of pediatric supratentorial ependymomas and is predominantly characterized by gene fusions involving RELA,[
Supratentorial ependymomas withYAP1fusions (ST-EPN-YAP1)
ST-EPN-YAP1 is the second, less common subset of supratentorial ependymomas and has fusions involving YAP1 on chromosome 11. ST-EPN-YAP1 is characterized by the following:
Supratentorial ependymomas without ZFTA or YAP1 fusions (on chromosome 11) are an undefined entity, and it is unclear what these samples represent. By DNA methylation analysis, these samples often cluster with other entities such as high-grade gliomas and embryonal tumors. Caution should be taken when diagnosing a supratentorial ependymoma that does not harbor a fusion involving chromosome 11.[
Spinal ependymoma withMYCNamplification (SP-EPN-MYCN)
SP-EPN-MYCN is rare, with only 27 cases reported.[
For information about the treatment of childhood ependymoma, see Childhood Ependymoma Treatment.
Molecular features of hepatoblastoma
Genomic findings related to hepatoblastoma include the following:
Gene expression and epigenetic profiling have been used to identify biological subtypes of hepatoblastoma and to evaluate the prognostic significance of these subtypes.[
Delineating the clinical applications of the genomic, transcriptomic, and epigenomic profiling methods described above for the risk classification of patients with hepatoblastoma will require independent validation, which is one of the objectives of the ongoing Paediatric Hepatic International Tumour Trial (PHITT [NCT03017326]).
Molecular features of hepatocellular carcinoma
Genomic findings related to hepatocellular carcinoma include the following:
TERT mutations were observed in two of four transitional liver cell tumor cases tested.[
To date, these genetic mutations have not been used to select therapeutic agents for investigation in clinical trials.
For information about the treatment of childhood liver cancer, see Childhood Liver Cancer Treatment.
Molecular Features of Osteosarcoma
The genomic landscape of osteosarcoma is distinct from that of other childhood cancers. Compared with many adult cancers, it is characterized by an exceptionally high number of structural variants with a relatively small number of single nucleotide variants.[
Key observations regarding the genomic landscape of osteosarcoma are summarized below:
Figure 7. 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 intra- and inter-chromosomal translocations. Credit: National Cancer Institute.
Genetic predisposition to osteosarcoma
Germline mutations in several genes are associated with susceptibility to osteosarcoma. Table 5 summarizes the syndromes and associated genes for these conditions. A recent multi-institutional genomic study of more than 1,200 patients with osteosarcoma revealed pathogenic or likely pathogenic germline variants in autosomal dominant cancer-susceptibility genes in 18% of patients. The frequency of these cancer-susceptibility genes was higher in children aged 10 years or younger.[
Mutations in TP53 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 TP53-associated LFS, osteosarcoma is the most common sarcoma in children and adolescents aged 6 to 19 years.[
Investigators analyzed whole-exome sequencing from the germline of 4,435 pediatric cancer patients at the St. Jude Children's Research Hospital and 1,127 patients from the National Cancer Institute's Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. They identified 24 patients (0.43%) who harbored loss-of-function RECQL4 variants, including 5 of 249 patients (2.0%) with osteosarcoma.[
|AML = acute myeloid leukemia; IL-1 = interleukin-1; MDS = myelodysplastic syndrome; RANKL = receptor activator of nuclear factor kappa beta ligand; TNF = tumor necrosis factor.|
| a Adapted from Kansara et al.[
||Rare inherited disorder characterized by short stature and sun-sensitive skin changes. Often presents with a long, narrow face, small lower jaw, large nose, and prominent ears.||15q26.1||BLM||DNA helicase|
||Inherited pure red cell aplasia. Patients at risk for MDS and AML. Associated with skeletal abnormalities such as abnormal facial features (flat nasal bridge, widely spaced eyes).||Ribosomal proteins||Ribosome production[
||Inherited mutation inTP53gene. Affected family members at increased risk of bone tumors, breast cancer, leukemia, brain tumors, and sarcomas.||17p13.1||TP53||DNA damage response|
||Excessive breakdown of bone with abnormal bone formation and remodeling, resulting in pain from weak, malformed bone.||18q21-qa22||LOH18CR1||IL-1/TNF signaling; RANKL signaling pathway|
||Malignant tumor of the retina. Approximately 66% of patients are diagnosed by age 2 years and 95% of patients by age 3 years. Patients with heritable germ cell mutations at greater risk of subsequent neoplasms.||13q14.2||RB1||Cell-cycle checkpoint|
|Rothmund-Thomson syndrome (also called poikiloderma congenitale)[
||Autosomal recessive condition. Associated with skin findings (atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, and skeletal abnormalities. Increased incidence of osteosarcoma at a younger age.||8q24.3||RECQL4||DNA helicase|
||Patients often have short stature and in their early twenties, develop signs of aging, including graying of hair and hardening of skin. Other aging problems such as cataracts, skin ulcers, and atherosclerosis develop later.||8p12-p11.2||WRN||DNA helicase; exonuclease activity|
For more information about these genetic syndromes, see the following summaries:
For information about the treatment of osteosarcoma, see Osteosarcoma and Undifferentiated Pleomorphic Sarcoma of Bone Treatment.
Molecular Features of Ewing Sarcoma
The detection of a translocation involving the EWSR1 gene on chromosome 22 band q12 and any one of a number of partner chromosomes is the key feature in the diagnosis of Ewing sarcoma (see Table 6).[
Besides these consistent aberrations involving the EWSR1 gene at 22q12, additional numerical and structural aberrations have been observed in Ewing sarcoma, including gains of chromosomes 2, 5, 8, 9, 12, and 15; the nonreciprocal translocation t(1;16)(q12;q11.2); and deletions on the short arm of chromosome 6. Trisomy 20 may be associated with a more aggressive subset of Ewing sarcoma.[
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.[
A discovery cohort (n = 99) highlighted the frequency of chromosome 8 gain, the co-occurrence of chromosome 1q gain and chromosome 16q loss, the mutual exclusivity of CDKN2A deletion and STAG2 mutation, and the relative paucity of recurrent single nucleotide variants for Ewing sarcoma.[
Ewing sarcoma translocations can all be found with standard cytogenetic analysis. A more rapid analysis looking for a break apart of the EWSR1 gene is now frequently done to confirm the diagnosis of Ewing sarcoma molecularly.[
Genome-wide association studies have identified susceptibility loci for Ewing sarcoma at 1p36.22, 10q21, and 15q15.[
|TET Family Partner||Fusion With ETS-Like Oncogene Partner||Translocation||Comment|
|a These partners are not members of the ETS family of oncogenes.|
|EWSR1||EWSR1::FLI1||t(11;22)(q24;q12)||Most common; approximately 85% to 90% of cases|
|EWSR1::ERG||t(21;22)(q22;q12)||Second most common; approximately 10% of cases|
For information about the treatment of Ewing sarcoma, see Ewing Sarcoma and Undifferentiated Small Round Cell Sarcomas of Bone and Soft Tissue Treatment.
Genomics of rhabdomyosarcoma
The four histological categories recognized in the 5th edition of the World Health Organization (WHO) Classification of Tumors of Soft Tissue and Bone have distinctive genomic alterations and are briefly summarized below.[
The distribution of gene mutations and gene amplifications (for CDK4 and MYCN) differs between patients with embryonal histology lacking a PAX::FOXO1 gene fusion (fusion-negative rhabdomyosarcoma) and patients with PAX::FOXO1 gene fusions (fusion-positive rhabdomyosarcoma). See Table 7 below and the text that follows. These frequencies are derived from a combined cohort of the Children's Oncology Group (COG) and United Kingdom rhabdomyosarcoma patients (n = 641).[
|Gene||% FN Cases With Gene Alteration||% FP Cases With Gene Alteration|
| a Adapted from Shern et al.[
Details of the genomic alterations that predominate within each of the WHO histological categories are as follows.
Among the RAS pathway genes, germline mutations in NF1 and HRAS predispose to rhabdomyosarcoma. In a study of 615 children with rhabdomyosarcoma, 347 had tumors with embryonal histology. Of these, nine patients had NF1 germline mutations, and five patients had HRAS germline mutations, representing 2.6% and 1.4% of embryonal histology cases, respectively.[
Other genes with recurring mutations in fusion-negative rhabdomyosarcoma tumors include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 15% of cases.[
TP53 mutations: TP53 mutations are observed in 10% to 15% of patients with fusion-negative rhabdomyosarcoma and occur less commonly (about 4%) in patients with alveolar rhabdomyosarcoma.[
The presence of TP53 mutations was associated with reduced EFS in both nonrisk-stratified and risk-stratified analyses for both a COG and a U.K. rhabdomyosarcoma cohort.[
Rhabdomyosarcoma is one of the childhood cancers associated with Li-Fraumeni syndrome. In a study of 614 pediatric patients with rhabdomyosarcoma, 11 patients (1.7%) had TP53 germline mutations. Mutations were less common in patients with alveolar histology (0.6%), compared with patients with nonalveolar histologies (2.2%).[
DICER1 mutations in embryonal rhabdomyosarcoma: DICER1 mutations are observed in a small subset of patients with embryonal rhabdomyosarcoma, most commonly arising in tumors of the female genitourinary tract.[
For the diagnosis of alveolar rhabdomyosarcoma, a FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situ hybridization or reverse transcription–polymerase chain reaction.[
In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[
Congenital/infantile spindle cell rhabdomyosarcoma: Several reports have described cases of congenital or infantile spindle cell rhabdomyosarcoma with gene fusions involving VGLL2 and NCOA2 (e.g., VGLL2::CITED2, TEAD1::NCOA2, VGLL2::NCOA2, SRF::NCOA2).[
MYOD1-mutant spindle cell/sclerosing rhabdomyosarcoma: In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients.[
Intraosseous spindle cell rhabdomyosarcoma: Primary intraosseous rhabdomyosarcoma is a very uncommon presentation for rhabdomyosarcoma. Most cases present with gene rearrangements involving TFCP2, with either FUS or EWSR1.[
For information about the treatment of childhood rhabdomyosarcoma, see Childhood Rhabdomyosarcoma Treatment.
Genomics of Langerhans Cell Histiocytosis (LCH)
Pulmonary LCH in adults was initially reported to be nonclonal in approximately 75% of cases,[
In a study of 117 patients with LCH, 83 patients with adult pulmonary LCH underwent molecular analysis. Nearly 90% of these patients had mutations in the MAPK pathway.[
Figure 8. Courtesy of Rikhia Chakraborty, Ph.D. Permission to reuse the figure in any form must be obtained directly from Dr. Chakraborty.
The theory for the genomic basis of LCH was advanced by a 2010 report of an activating mutation of the BRAF oncogene (V600E) that was detected in 35 of 61 cases (57%).[
The RAS-MAPK signaling pathway (see Figure 8) transmits signals from a cell surface receptor (e.g., a growth factor) through the RAS pathway (via one of the RAF proteins [A, B, or C]) to phosphorylate MEK and then the extracellular signal-regulated kinase (ERK), which leads to nuclear signals affecting cell cycle and transcription regulation. The V600E mutation of BRAF leads to continuous phosphorylation, and thus activation, of MEK and ERK without the need for an external signal. Activation of ERK occurs by phosphorylation, and phosphorylated ERK can be detected in virtually all LCH lesions.[
The presence of the BRAF V600E mutation in blood and bone marrow was studied in a series of 100 patients, 65% of whom tested positive for the BRAF V600E mutation by a sensitive quantitative polymerase chain reaction technique.[
The myeloid dendritic cell origin of LCH was confirmed by finding CD34-positive stem cells with the mutation in the bone marrow of high-risk patients. In those with low-risk disease, the mutation was found in more mature myeloid dendritic cells, suggesting that the stage of cell development at which the somatic mutation occurs is critical in defining the extent of disease in LCH. LCH is now generally considered to represent a myeloid neoplasm.
Other RAS-MAPK pathway alterations
Because RAS-MAPK pathway activation can be detected in all LCH cases, but not all cases have BRAF mutations, the presence of genomic alterations in other components of the pathway was suspected. The following genomic alterations were identified:
Another study showed MAP2K1 mutations exclusively in 11 of 22 BRAF–wild-type cases.[
Studies support the universal activation of ERK in LCH; ERK activation in most cases is explained by BRAF and MAP2K1 alterations.[
Clinical implications of the described genomic findings include the following:
Case reports and case series have described the activity of BRAF inhibitors in adult patients with LCH [
Several case reports and two case series have demonstrated the efficacy of BRAF inhibitors for the treatment of LCH in children.[
For information about the treatment of childhood LCH, see Langerhans Cell Histiocytosis Treatment.
Molecular features of neuroblastoma
Children with neuroblastoma can be divided into subsets with different predicted risks of relapse on the basis of clinical factors and biological markers at the time of diagnosis.
Key genomic characteristics of high-risk neuroblastoma that are discussed below include the following:
Segmental chromosomal aberrations
Segmental chromosomal aberrations, found most frequently in 1p, 2p, 1q, 3p, 11q, 14q, and 17p, are best detected by comparative genomic hybridization. These aberrations are seen in most high-risk and/or stage 4 neuroblastoma tumors.[
In an analysis of localized, resectable, non-MYC amplified neuroblastoma, cases from two consecutive European studies and a North American cohort (including INSS stages 1, 2A, and 2B) were analyzed for segmental chromosome aberrations (namely gain of 1q, 2p, and 17q and loss of 1p, 3p, 4p, and 11q). The study revealed a different prognostic impact of tumor genomics depending on patient age (<18 months or >18 months). Patients were treated with surgery alone regardless of a tumor residuum.[
In a study of children older than 12 months who had unresectable primary neuroblastomas without metastases, segmental chromosomal aberrations were found in most patients. 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 EFS but not on OS. However, in children older than 18 months, there was a significant difference in OS between children with segmental chromosomal aberrations (67%) and children without segmental chromosomal aberrations (100%), regardless of tumor histology.[
Segmental chromosomal aberrations are also predictive of recurrence in infants with localized unresectable or metastatic neuroblastoma without MYCN gene amplification.[
In an analysis of intermediate-risk patients in a Children's Oncology Group (COG) study, 11q loss, but not 1p loss, was associated with reduced EFS but not OS (11q loss and no 11q loss: 3-year EFS rates, 68% and 85%, respectively; P = .022; 3-year OS rates, 88% and 94%, respectively; P = .09).[
An international collaboration studied 556 patients with high-risk neuroblastoma and identified two types of segmental copy number aberrations that were associated with extremely poor outcome. Distal 6q losses were found in 6% of patients and were associated with a 10-year survival rate of only 3.4%. Amplifications of regions not encompassing the MYCN locus, in addition to MYCN amplification, were detected in 18% of the patients and were associated with a 10-year survival rate of 5.8%.[
MYCN amplification is detected in 16% to 25% of neuroblastoma tumors.[
In all stages of disease, amplification of the MYCN 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-tumor MYCN-amplified cohort, patients with hyperdiploid tumors have better outcomes than do patients with diploid tumors.[
Most unfavorable clinical and pathobiological features are associated, to some degree, with MYCN amplification. In a multivariable logistic regression analysis of 7,102 patients in the International Neuroblastoma Risk Group (INRG) study, pooled segmental chromosomal aberrations and gains of 17q were poor prognostic features, even when not associated with MYCN amplification. However, another poor prognostic feature, segmental chromosomal aberrations at 11q, are almost entirely mutually exclusive of MYCN amplification.[
In a cohort of 6,223 patients from the INRG database with known MYCN status, the OS hazard ratio (HR) associated with MYCN amplification was 6.3 (95% confidence interval [CI], 5.7–7.0; P < .001). The greatest adverse prognostic impact of MYCN amplification for OS was in the youngest patients (aged <18 months: HR, 19.6; aged ≥18 months: HR, 3.0). Patients whose outcome was most impacted by MYCN status were those with otherwise favorable features, including age younger than 18 months, high mitosis karrhyohexis index, and low ferritin.[
Intratumoral heterogeneous MYCN amplification (hetMNA) refers to the coexistence of MYCN-amplified cells as a cluster or as single scattered cells and non-MYCN–amplified tumor cells. HetMNA has been reported infrequently. It can occur spatially within the tumor as well as between the tumor and the metastasis at the same time or temporally during the disease course. The International Society of Paediatric Oncology Europe Neuroblastoma (SIOPEN) biology group investigated the prognostic significance of this neuroblastoma subtype. Tumor tissue from 99 patients identified as having hetMNA and diagnosed between 1991 and 2015 was analyzed to elucidate the prognostic significance of MYCN-amplified clones in otherwise non-MYCN–amplified neuroblastomas. Patients younger than 18 months showed a better outcome in all stages compared with older patients. The genomic background correlated significantly with relapse frequency and OS. No relapses occurred in cases of only numerical chromosomal aberrations. This study suggests that hetMNA tumors have to be evaluated in the context of the genomic tumor background in combination with the clinical pattern, including the patient's age and disease stage. Future studies are needed in patients younger than 18 months who have localized disease with hetMNA.[
FOXR2 gene expression is observed in approximately 8% of neuroblastoma cases. FOXR2 gene expression is normally absent postnatally, with the exception of male reproductive tissues.[
Neuroblastoma with FOXR2 activation is observed at comparable rates in high-risk and non–high-risk cases.[
Exonic mutations in neuroblastoma (includingALKmutations and amplification)
Multiple reports have documented that a minority of high-risk neuroblastomas have a low incidence of recurrently mutated genes. The most commonly mutated gene is ALK, which is mutated in approximately 10% of patients (see below). Other genes with even lower frequencies of mutations include ATRX, PTPN11, ARID1A, and ARID1B.[
Figure 9. 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 ALK gene provides instructions for making a cell surface receptor tyrosine kinase, expressed at significant levels only in developing embryonic and neonatal brains. ALK is the exonic mutation found most commonly in neuroblastoma. Germline mutations in ALK have been identified as the major cause of hereditary neuroblastoma. Somatically acquired ALK-activating exonic mutations are also found as oncogenic drivers in neuroblastoma.[
Two large cohort studies examined the clinical correlates and prognostic significance of ALK alterations. One study from the COG examined ALK status in 1,596 diagnostic neuroblastoma samples across all risk groups.[
In a study that compared the genomic data of primary diagnostic neuroblastomas originating in the adrenal gland (n = 646) with that of neuroblastomas originating in the thoracic sympathetic ganglia (n = 118), 16% of thoracic tumors harbored ALK mutations.[
Small-molecule ALK kinase inhibitors such as lorlatinib (added to conventional therapy) are being tested in patients with recurrent ALK-mutated neuroblastoma (NCT03107988) and in patients with newly diagnosed high-risk neuroblastoma with activated ALK (COG ANBL1531).[
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 neuroblastoma tumor samples to define somatic genetic alterations associated with relapse,[
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 (78%) relapse samples. Aberrations were found in ALK (n = 10), NF1 (n = 2), and one each in NRAS, KRAS, HRAS, BRAF, PTPN11, and FGFR1. Even with deep sequencing, 7 of the 18 alterations were not detectable in the primary tumor, highlighting the evolution of mutations presumably leading to relapse and the importance of genomic evaluations of tissues obtained at relapse.
A report that evaluated telomere maintenance mechanisms found that the proportion of cases with alternative lengthening of telomeres (ALT) activation was markedly higher in a cohort of relapsed patients than a cohort of newly diagnosed patients (48% vs. 10%, respectively).[
In a deep-sequencing study, 276 neuroblastoma samples (comprised of all stages and from patients of all ages at diagnosis) underwent very deep (33,000X) sequencing of just two amplified ALK mutational hot spots, which revealed 4.8% clonal mutations and an additional 5% subclonal mutations. This finding suggests that subclonal ALK gene mutations are common.[
Genomic alterations promoting telomere maintenance
Lengthening of telomeres, the tips of chromosomes, promotes cell survival. Telomeres otherwise shorten with each cell replication, eventually resulting in the cell's inability to replicate. Patients whose tumors lack telomere maintenance mechanisms have an excellent prognosis, while patients whose tumors harbored telomere maintenance mechanisms have a substantially worse prognosis.[
ALT-positive tumors in pediatric populations rarely present before the age of 18 months and occur almost exclusively in older children (median age at diagnosis, approximately 8 years).[
The prognosis for high-risk patients with ALT activation is as poor as that for patients with MYCN amplification for EFS;[
Additional biological factors associated with prognosis
MYC and MYCN expression
Immunostaining for MYC and MYCN proteins on a restricted subset of 357 undifferentiated/poorly differentiated neuroblastoma tumors demonstrated that elevated MYC/MYCN protein expression is prognostically significant.[
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 the antibody's antineuroblastoma activity, are often used to help treat patients with neuroblastoma. The clinical effectiveness of one such antibody led to the U.S. Food and Drug Administration approval of dinutuximab. The patient response to immunotherapy may be caused, in part, by variation in immune function among patients. One anti-GD2 antibody, termed 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 (KIR) subtypes.[
For information about the treatment of neuroblastoma, see Neuroblastoma Treatment.
Genomics of Retinoblastoma
Retinoblastoma is a tumor that occurs in heritable (25%–30%) and nonheritable (70%–75%) forms. Heritable disease is defined by the presence of a germline mutation of the RB1 gene. This germline mutation may have been inherited from an affected progenitor (25% of cases) or may have occurred in a germ cell before conception or in utero during early embryogenesis in patients with sporadic disease (75% of cases). The presence of positive family history or bilateral or multifocal disease is suggestive of heritable disease.
Heritable retinoblastoma may manifest as unilateral or bilateral disease. The penetrance of the RB1 mutation (laterality, age at diagnosis, and number of tumors) is probably dependent on concurrent genetic modifiers such as MDM2 and MDM4 polymorphisms.[
Children with heritable retinoblastoma tend to be diagnosed at a younger age than are children with the nonheritable form of the disease.
The genomic landscape of retinoblastoma is driven by alterations in RB1 that lead to biallelic inactivation.[
Recurrent changes in genes other than RB1 are uncommon in retinoblastoma but do occur. Mutations or deletions of BCOR and amplification of MYCN are the most frequently reported events.[
Genetic counseling is recommended for all patients with retinoblastoma. For more information, see the Genetic Counseling section.
For information about the treatment of retinoblastoma, see Retinoblastoma Treatment.
Molecular Features of Wilms Tumor
A Wilms tumor may arise during embryogenesis on the background of an otherwise genomically normal kidney, or it may arise from nongermline somatic genetic precursor lesions residing in histologically and functionally normal kidney tissue. Hypermethylation of H19, a known component of a subset of Wilms tumors, is a very common genetic abnormality found in these normal-appearing areas of precursor lesions.[
One study performed genome-wide sequencing, mRNA and miRNA expression, DNA copy number, and methylation analysis on 117 Wilms tumors, followed by targeted sequencing of 651 Wilms tumors.[
Approximately one-third of Wilms tumor cases involve mutations in WT1, CTNNB1, or AMER1 (WTX).[
Elevated rates of Wilms tumor are observed in patients with a number of genetic disorders, including WAGR (Wilms tumor, aniridia, genitourinary anomalies, and mental retardation) syndrome (WAGR spectrum), Beckwith-Wiedemann syndrome, hemihypertrophy, Denys-Drash syndrome, and Perlman syndrome.[
The genomic and genetic characteristics of Wilms tumor are summarized below.
The WT1 gene is located on the short arm of chromosome 11 (11p13). WT1 is a transcription factor that is required for normal genitourinary development and is important for differentiation of the renal blastema.[
Wilms tumor with a WT1 mutation is characterized by the following:
Germline WT1 mutations are more common in children with Wilms tumor and one of the following:
Germline WT1 point mutations produce genetic syndromes that are characterized by nephropathy, 46XY disorder of sex development, and varying risks of Wilms tumor.[
Inactivating mutations or deletions in the PAX6 gene lead to aniridia, while deletion of WT1 confers the increased risk of Wilms tumor. Loss of the LMO2 gene has been associated with a more frequent development of Wilms tumor in patients with congenital aniridia and WAGR-region deletions.[
Wilms tumor in children with WAGR syndrome is characterized by an excess of bilateral disease, intralobar nephrogenic rests, early age at diagnosis, and stromal-predominant histology in FH tumors.[
WT1 mutations in Denys-Drash syndrome are most often missense mutations in exons 8 and 9, which code for the DNA binding region of WT1.[
WT1 mutations in Frasier syndrome typically occur in intron 9 at the KT site, and create an alternative splicing variant, thereby preventing production of the usually more abundant WT1 +KTS isoform.[
Studies evaluating genotype/phenotype correlations of WT1 mutations have shown that the risk of Wilms tumor is highest for truncating mutations (14 of 17 cases, 82%) and lower for missense mutations (27 of 67 cases, 42%). The risk is lowest for KTS splice site mutations (1 of 27 cases, 4%).[
CTNNB1 is one of the most commonly mutated genes in Wilms tumor, reported to occur in 15% of patients with Wilms tumor.[
AMER1(WTX) gene on the X chromosome
AMER1 is located on the X chromosome at Xq11.1. It is altered in 15% to 20% of Wilms tumor cases.[
AMER1 alterations are equally distributed between males and females, and AMER1 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, WT2, maps to an imprinted region of chromosome 11p15.5. When it is a germline mutation, it causes Beckwith-Wiedemann syndrome. About 3% of children with Wilms 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 one-fifth of patients with Beckwith-Wiedemann syndrome who develop Wilms tumor present with bilateral disease, and metachronous bilateral disease is also observed.[
Approximately 80% of patients with Beckwith-Wiedemann syndrome have a molecular defect of the 11p15 domain.[
Several candidate genes at the WT2 locus comprise the two independent imprinted domains: IGF2 and H19; and CDKN1C and KCNQ1OT1.[
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 following four main molecular subtypes of Beckwith-Wiedemann syndrome are characterized by specific genotype-phenotype correlations:
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.[
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:
In an analysis of FH Wilms tumor from 1,114 patients from NWTS-5 (COG-Q9401/NCT00002611), 28% of the tumors displayed 1q gain.[
One study included a cohort of FH Wilms tumor that was enriched for patients who relapsed. The study found that the prevalence of 1q gain was higher in the relapsed Wilms tumor specimens (75%) than in the matched primary samples (47%).[
These conflicting results may arise from the greater prognostic significance of 1q gain described above. LOH of 16q and 1p loses significance as independent prognostic markers in the presence of 1q gain. However, in the absence of 1q gain, LOH of 16q and 1p retains their adverse prognostic impact.[
Germline mutations in miRNAPG are observed for DICER1 and DIS3L2, with mutations in the former causing DICER1 syndrome and mutations in the latter causing Perlman syndrome.
Figure 10. 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 http://creativecommons.org/licenses/by-nc/4.0/.
In a study of 118 prospectively identified patients with diffuse anaplastic Wilms tumor registered on the NWTS-5 trial, 57 patients (48%) demonstrated TP53 mutations, 13 patients (11%) demonstrated TP53 segmental copy number loss without mutations, and 48 patients (41%) lacked both (wild-type TP53 [wtTP53]). All TP53 mutations were detected by sequencing alone. Patients with stage III or stage IV disease with wtTP53 had a significantly lower relapse rate and mortality rate than did patients with TP53 abnormalities (P = .00006 and P = .00007, respectively). The TP53 status had no effect on patients with stage I or stage II tumors.[
Figure 11 summarizes the genomic landscape of a selected cohort of Wilms tumor patients selected because they experienced relapse despite showing FH.[
Figure 11. 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 http://creativecommons.org/licenses/by/4.0/.
Genomic alterations in Wilms tumor at relapse
Wilms tumor at relapse appears to maintain most of the genomic alterations present at diagnosis, although there may be changes in the prevalence of alterations in specific genes between diagnosis and relapse.[
Genomic alterations in adults with Wilms tumor
Wilms tumor in patients older than 16 years is rare, with an incidence rate of less than 0.2 cases per 1 million people per year.[
In a study of 14 patients with a Wilms tumor diagnosis who were older than 16 years (range, 17–46 years; median age, 31 years), 5 patients (36%) harbored BRAF V600E mutations. While BRAF V600E mutations are extremely uncommon in pediatric Wilms tumor, they are present in 90% of metanephric adenomas of the kidney, a typically benign condition arising almost exclusively in adults.[
Another report described renal tumors that had histological overlap between metanephric adenoma and epithelial Wilms tumor.[
For information about the treatment of Wilms tumor, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.
Renal Cell Carcinoma
Molecular features of 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 single-institution investigation, molecular data from 22 patients with translocation-positive RCCs were pooled with previously published data. Investigators found that certain copy-number variations were associated with disease aggressiveness in patients with translocation-positive RCCs. Tumors bearing 9p loss, 17q gain, or a genetically high burden of copy-number variations were associated with poor survival in these patients. Three pediatric patients who had an indolent disease course were included in the study and were found to have lower copy-number burdens, which supports the less-aggressive disease course in these patients, as compared with adult patients.[
Another less-common translocation subtype, t(6;11)(p21;q12), involving a TFEB gene fusion, induces overexpression of TFEB. The translocations involving TFE3 and TFEB 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 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 translocation-positive RCC is treated with surgery alone despite presenting at a more advanced stage (III/IV), a meta-analysis reported that these patients have poorer outcomes.[
Diagnosis of Xp11 translocation RCC needs to be confirmed by a molecular genetic approach, rather than using TFE3 immunohistochemistry alone, because reported cases have lacked the translocation.
There is a rare subset of RCC cases that is positive for TFE3 and lack a TFE3 translocation, showing an ALK 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:[
For information about the treatment of renal cell carcinoma, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.
Rhabdoid Tumors of the Kidney
Molecular features of rhabdoid tumors of the kidney
Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1 gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[
Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[
In a study of 100 patients with rhabdoid tumors of the brain, kidney, or soft tissues, 35 were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma. Two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.[
Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[
For information about the treatment of rhabdoid tumor of the kidney, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.
Clear Cell Sarcoma of the Kidney
Molecular features of clear cell sarcoma of the kidney
The molecular background of clear cell sarcoma of the kidney is poorly understood because of its rarity and lack of experimental models. However, several molecular features of clear cell sarcoma of the kidney have been described, including the following:
For information about the treatment of clear cell tumor of the kidney, see Wilms Tumor and Other Childhood Kidney Tumors Treatment.
For information about the genomics of childhood multiple endocrine neoplasia (MEN) syndromes, see the Clinical Presentation, Diagnostic Evaluation, and Molecular Features section in Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.
For information about the treatment of childhood MEN syndromes, see Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.
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.
Added text to the Acute Lymphoblastic Leukemia (ALL) section to state that throughout this section, the percentages of genomic subtypes from among all B-ALL and T-ALL cases are derived primarily from a report describing the genomic characterization of patients treated on several Children's Oncology Group (COG) and St. Jude Children's Research Hospital (SJCRH) clinical trials. Percentages by subtype are presented for National Cancer Institute (NCI) standard-risk and NCI high-risk patients with B-ALL (cited Brady et al. as reference 1).
Revised text in the ALL section to state that Figures 1 and 2 illustrate the distribution of NCI standard-risk and high-risk B-ALL cases by 23 cytogenetic/molecular subtypes. The two most common subtypes together account for approximately 60% of NCI standard-risk B-ALL cases, but only approximately 25% of NCI high-risk cases. Most other subtypes are much less common, with most occurring at frequencies less than 2% to 3% of B-ALL cases.
Added Figure 1 to the ALL section, depicting the genomic subtypes and frequencies of NCI standard-risk B-ALL.
Added Figure 2 to the ALL section, depicting the genomic subtypes and frequencies of NCI high-risk B-ALL.
Revised text in the ALL section to state that high hyperdiploidy, defined as 51 to 65 chromosomes per cell or a DNA index greater than 1.16, occurs in approximately 33% of NCI standard-risk and 14% of NCI high-risk pediatric B-ALL cases.
Added text to the ALL section to state that a retrospective analysis evaluated patients treated on two consecutive UKALL trials to identify and validate a profile to predict outcome in high hyperdiploid B-ALL. The investigators defined a good-risk group that was associated with a more favorable prognosis. Good-risk patients had either trisomies of both chromosomes 17 and 18 or trisomy of one of these two chromosomes along with absence of trisomies of chromosomes 5 and 20. All other patients were defined as poor risk and had a less favorable outcome. End-induction minimal residual disease and copy number alterations were prognostically significant within each hyperdiploid risk group (cited Enshaei et al. as reference 26).
Added text to the ALL section to state that near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.
Added text to the ALL section to state that low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.
Revised text to the ALL section to state that fusion of the ETV6 gene on chromosome 12 to the RUNX1 gene on chromosome 21 is present in approximately 27% of NCI standard-risk and 10% of NCI high-risk pediatric B-ALL cases.
Added text to the ALL section to state that the BCR::ABL1 fusion occurs in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.
Added text to the ALL section to state that beyond infancy, approximately 1% of NCI standard-risk and 4% of NCI high-risk pediatric B-ALL cases have KMT2A rearrangements.
Added Attarbaschi et al. as reference 66 in the ALL section.
Revised text in the ALL section to state that fusion of the TCF3 gene on chromosome 19 to the PBX1 gene on chromosome 1 is present in approximately 4% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.
Revised text in the ALL section to state that approximately 3% of NCI standard-risk and 6% of NCI high-risk pediatric B-ALL patients have a rearrangement involving DUX4 that leads to its overexpression.
Revised text in the ALL section to state that gene fusions involving MEF2D, a transcription factor that is expressed during B-cell development, are observed in approximately 0.3% of NCI standard-risk and 3% of NCI high-risk pediatric B-ALL cases.
Revised text in the ALL section to state that NF384 is a transcription factor that is rearranged in approximately 0.3% of NCI standard-risk and 2.7% of NCI high-risk pediatric B-ALL cases.
Revised text in the ALL section to state that iAMP21 occurs in approximately 5% of NCI standard-risk and 7% of NCI high-risk pediatric B-ALL cases.
Revised text in the ALL section to state that PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.
Revised text in the ALL section to state that cases with PAX5 p.P80R represent approximately 0.3% of NCI standard-risk and 1.8% of NCI high-risk pediatric B-ALL. PAX5 p.P80R B-ALL appears to occur more frequently in the adolescent and young adult (AYA) and adult populations.
Revised text in the ALL section to state that the hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations and half of those cases containing concomitant JAK mutations.
Added text to the ALL section to state that BCR::ABL1-like ALL cases with non-CRLF2 genomic alterations represent approximately 3% of NCI standard-risk and 8% of NCI high-risk pediatric B-ALL cases.
Added text to the ALL section to state that BCR::ABL1-like B-ALL with CRLF2 genomic alterations is observed in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.
Editorial changes were made to this section.
Revised text in the Neuroblastoma section to state that segmental chromosomal aberrations, found most frequently in 1p, 2p, 1q, 3p, 11q, 14q, and 17p, are best detected by comparative genomic hybridization. These aberrations are seen in most high-risk and/or stage 4 neuroblastoma tumors (cited Irwin et al. as reference 9).
Added text to the Neuroblastoma section to state that in the ANBL00B1 study of 4,832 newly diagnosed patients enrolled between 2007 to 2017, the 5-year event-free survival (EFS) and overall survival (OS) rates were 77% and 87%, respectively, for patients whose tumors were MYCN nonamplified. In comparison, the 5-year EFS and OS rates were 51% and 57%, respectively, for patients whose tumors were MYCN amplified.
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® Cancer Information for Health Professionals pages.
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 in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
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Board members review recently published articles each month to determine whether an article should:
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.
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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Cancer Genomics. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/childhood-cancers/pediatric-genomics-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 27466641]
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Last Revised: 2023-02-17
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