References

1. Northcott PA, Lee C, Zichner T, et al.: Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511 (7510): 428-34, 2014. [PMC free article: PMC4201514] [PubMed: 25043047]
2. Chen X, Bahrami A, Pappo A, et al.: Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep 7 (1): 104-12, 2014. [PMC free article: PMC4096827] [PubMed: 24703847]
3. Mody RJ, Wu YM, Lonigro RJ, et al.: Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA 314 (9): 913-25, 2015. [PMC free article: PMC4758114] [PubMed: 26325560]
4. Parsons DW, Roy A, Yang Y, et al.: Diagnostic Yield of Clinical Tumor and Germline Whole-Exome Sequencing for Children With Solid Tumors. JAMA Oncol 2 (5): 616-624, 2016. [PMC free article: PMC5471125] [PubMed: 26822237]
5. Zhang J, Walsh MF, Wu G, et al.: Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med 373 (24): 2336-46, 2015. [PMC free article: PMC4734119] [PubMed: 26580448]

Acute Lymphoblastic Leukemia (ALL)

B-ALL cytogenetics/genomics

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.[1] Figures 1 and 2 illustrate the distribution of NCI standard-risk and high-risk B-ALL cases by 23 cytogenetic/molecular subtypes.[1] The two most common subtypes (hyperdiploid and ETV6::RUNX1 fusion) 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. The molecular and clinical characteristics of some of the subtypes are discussed below.

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).[2]

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:

• IKZF1 deletions and mutations are most commonly observed within cases of BCR::ABL1 ALL and BCR::ABL1-like ALL.[3,4]
• Intragenic ERG deletions occur within a distinctive subtype characterized by gene rearrangements involving DUX4.[5,6]
• TP53 mutations, often germline, occur at high frequency in patients with low hypodiploid ALL with 32 to 39 chromosomes.[7] TP53 mutations are uncommon in other patients with B-ALL.

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.[4,8,9] Several kinase genes and cytokine receptor genes are activated by translocations, as described below in the discussion of BCR::ABL1 ALL and BCR::ABL1-like ALL. FLT3 mutations occur in a minority of cases (approximately 10%) of hyperdiploid ALL and KMT2A-rearranged ALL, and are rare in other subtypes.[10]

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.[11] However, molecular subtype–defining lesions such as translocations and aneuploidy are almost always retained at relapse.[1,11] Of particular importance are new mutations that arise at relapse that may be selected by specific components of therapy. As an example, mutations in NT5C2 are not found at diagnosis, whereas specific mutations in NT5C2 were observed in 7 of 44 (16%) and 9 of 20 (45%) cases of B-ALL with early relapse that were evaluated for this mutation in two studies.[11,12] NT5C2 mutations are uncommon in patients with late relapse, and they appear to induce resistance to mercaptopurine and thioguanine.[12] Another gene that is found mutated only at relapse is PRSP1, a gene involved in purine biosynthesis.[13] Mutations were observed in 13.0% of a Chinese cohort and 2.7% of a German cohort, and were observed in patients with on-treatment relapses. The PRSP1 mutations observed in relapsed cases induce resistance to thiopurines in leukemia cell lines. CREBBP mutations are also enriched at relapse and appear to be associated with increased resistance to glucocorticoids.[11,14] With increased understanding of the genomics of relapse, it may be possible to tailor upfront therapy to avoid relapse or detect resistance-inducing mutations early and intervene before a frank relapse.

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.[15][Level of evidence B4] Other alterations historically have been associated with a poorer prognosis, including the BCR::ABL1 fusion (Philadelphia chromosome–positive [Ph+]; t(9;22)(q34;q11.2)), rearrangements of the KMT2A gene, hypodiploidy, and intrachromosomal amplification of the RUNX1 gene (iAMP21).[16]

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:[17]

• B-lymphoblastic leukemia/lymphoma, NOS.
• B-lymphoblastic leukemia/lymphoma with high hyperdiploidy.
• B-lymphoblastic leukemia/lymphoma with hypodiploidy.
• B-lymphoblastic leukemia/lymphoma with iAMP21.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1 fusion.
• B-lymphoblastic leukemia/lymphoma with BCR::ABL1-like features.
• B-lymphoblastic leukemia/lymphoma with KMT2A rearrangement.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1 fusion.
• B-lymphoblastic leukemia/lymphoma with ETV6::RUNX1-like features.
• B-lymphoblastic leukemia/lymphoma with TCF3::PBX1 fusion.
• B-lymphoblastic leukemia/lymphoma with IGH::IL3 fusion.
• B-lymphoblastic leukemia/lymphoma with TCF3::HLF fusion.
• B-lymphoblastic leukemia/lymphoma with other defined genetic abnormalities.

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.

1. Chromosome number.

   • High hyperdiploidy (51–65 chromosomes).
     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.[1,18] Hyperdiploidy can be evaluated by measuring the DNA content of cells (DNA index) or by karyotyping. In cases with a normal karyotype or in which standard cytogenetic analysis was unsuccessful, interphase fluorescence in situ hybridization (FISH) may detect hidden hyperdiploidy.
     High hyperdiploidy generally occurs in cases with clinically favorable prognostic factors (patients aged 1 to <10 years with a low white blood cell [WBC] count) and is an independent favorable prognostic factor.[18-20] Within the hyperdiploid range of 51 to 65 chromosomes, patients with higher modal numbers (58–66) appeared to have a better prognosis in one study.[20] Hyperdiploid leukemia cells are particularly susceptible to undergoing apoptosis and accumulate higher levels of methotrexate and its active polyglutamate metabolites,[21] which may explain the favorable outcome commonly observed in these cases.
     While the overall outcome of patients with high hyperdiploidy is considered to be favorable, factors such as age, WBC count, specific trisomies, and early response to treatment have been shown to modify its prognostic significance.[22,23]
     Multiple reports have described the prognostic significance of specific chromosome trisomies among children with hyperdiploid B-ALL.

     • A study combining experience from the Children's Cancer Group and the Pediatric Oncology Group (POG) found that patients with trisomies of chromosomes 4, 10, and 17 (triple trisomies) have a particularly favorable outcome.[24]; [15][Level of evidence B4]
     • A report using POG data found that NCI standard-risk patients with trisomies of 4 and 10, without regard to chromosome 17 status, have an excellent prognosis.[25] COG protocols currently use double trisomies of chromosomes 4 and 10 to define favorable hyperdiploidy.
     • 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 (approximately 80% of high hyperdiploidy patients) 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 MRD and copy number alterations (such as IKZF1 deletion) were prognostically significant within each hyperdiploid risk group.[26]
     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,[27] and the outcome of these patients (treated without tyrosine kinase inhibitors) was inferior to that observed in non-BCR::ABL1 high hyperdiploid patients.
     Certain patients with hyperdiploid ALL may have a hypodiploid clone that has doubled (masked hypodiploidy).[28] Molecular technologies, such as single nucleotide polymorphism microarrays to detect widespread loss of heterozygosity, can be used to identify patients with masked hypodiploidy.[28] These cases may be interpretable based on the pattern of gains and losses of specific chromosomes (hyperdiploidy with two and four copies of chromosomes rather than three copies). These patients have an unfavorable outcome, similar to those with hypodiploidy.[29]
     Near triploidy (68–80 chromosomes) and near tetraploidy (>80 chromosomes) are much less common and appear to be biologically distinct from high hyperdiploidy.[30] Unlike high hyperdiploidy, a high proportion of near tetraploid cases harbor a cryptic ETV6::RUNX1 fusion.[30-32] Near triploidy and tetraploidy were previously thought to be associated with an unfavorable prognosis, but later studies suggest that this may not be the case.[30,32]
     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.[1,33]
   • Hypodiploidy (<44 chromosomes).
     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:[29]

     • Near-haploid: 24 to 29 chromosomes (n = 46).
     • Low-hypodiploid: 33 to 39 chromosomes (n = 26).
     • High-hypodiploid: 40 to 43 chromosomes (n = 13).
     • Near-diploid: 44 chromosomes (n = 54).
     Near-haploid cases represent approximately 2% of NCI standard-risk and 2% of NCI high-risk pediatric B-ALL.[1]
     Low-hypodiploid cases represent approximately 0.5% of NCI standard-risk and 2.6% of NCI high-risk pediatric B-ALL cases.[1]
     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.[29,34] Patients with fewer than 44 chromosomes have a worse outcome than do patients with 44 or 45 chromosomes in their leukemic cells.[29] A number of studies have shown that patients with high minimal residual disease (MRD) (≥0.01%) after induction do very poorly, with 5-year event-free survival (EFS) rates ranging from 25% to 47%. Although hypodiploid patients with low MRD after induction fare better (5-year EFS rates, 64%–75%), their outcomes are still inferior to most children with other types of ALL.[35-37]
     The recurring genomic alterations of near-haploid and low-hypodiploid ALL appear to be distinctive from each other and from other types of ALL.[7] In near-haploid ALL, alterations targeting RTK signaling, RAS signaling, and IKZF3 are common.[38] In low-hypodiploid ALL, genetic alterations involving TP53, RB1, and IKZF2 are common. Importantly, the TP53 alterations observed in low-hypodiploid ALL are also present in nontumor cells in approximately 40% of cases, suggesting that these mutations are germline and that low-hypodiploid ALL represents, in some cases, a manifestation of Li-Fraumeni syndrome.[7] Approximately two-thirds of patients with ALL and germline pathogenic TP53 variants have hypodiploid ALL.[39]
2. Chromosomal translocations and gains/deletions of chromosomal segments.

   • ETV6::RUNX1 fusion (t(12;21)(p13.2;q22.1)).
     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.[1,31]
     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.[40,41] Hispanic children with ALL have a lower incidence of ETV6::RUNX1 fusions than do White children.[42]
     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:[43-47]; [15][Level of evidence B4]

     -

     Early response to treatment.

     -

     NCI risk category (age and WBC count at diagnosis).

     -

     Treatment regimen.

     In one study of the treatment of newly diagnosed children with ALL, multivariate analysis of prognostic factors found age and leukocyte count, but not ETV6::RUNX1 fusion status, to be independent prognostic factors.[43] However, another large trial only enrolled patients classified as having favorable-risk B-ALL, with low-risk clinical features, either trisomies of 4, 10, and 17 or ETV6::RUNX1 fusion, and end induction MRD less than 0.01%. Patients had a 5-year continuous complete remission rate of 93.7% and a 6-year OS rate of 98.2% for patients with ETV6::RUNX1.[15] It does not appear that the presence of secondary cytogenetic abnormalities, such as deletion of ETV6 (12p) or CDKN2A/B (9p), impacts the outcome of patients with the ETV6::RUNX1 fusion.[47,48]
     There is a higher frequency of late relapses in patients with ETV6::RUNX1 fusions compared with other relapsed B-ALL patients.[43,49] Patients with the ETV6::RUNX1 fusion who relapse seem to have a better outcome than other relapse patients,[50] with an especially favorable prognosis for patients who relapse more than 36 months from diagnosis.[51] Some relapses in patients with ETV6::RUNX1 fusions may represent a new independent second hit in a persistent preleukemic clone (with the first hit being the ETV6::RUNX1 translocation).[52,53]
   • BCR::ABL1 fusion (t(9;22)(q34.1;q11.2); Ph+).
     The BCR::ABL1 fusion leads to production of a BCR::ABL1 fusion protein with tyrosine kinase activity (see Figure 3).[1] The BCR::ABL1 fusion occurs in approximately 2% of NCI standard-risk and 5% of NCI high-risk pediatric B-ALL cases.[1]

     

     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.[27,54-56] Inhibitors of the BCR::ABL1 tyrosine kinase, such as imatinib mesylate, are effective in patients with BCR::ABL1 ALL.[57] A study by the Children's Oncology Group (COG), which used intensive chemotherapy and concurrent imatinib mesylate given daily, demonstrated a 5-year EFS rate of 70% (± 12%), which was superior to the EFS rate of historical controls in the pre-tyrosine kinase inhibitor (imatinib mesylate) era. This result eliminated the recommendation of HSCT for patients with a good early response to chemotherapy using a tyrosine kinase inhibitor.[58,59]
   • KMT2A-rearranged ALL (t(v;11q23.3)).
     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.[1]
     These rearrangements are generally associated with an increased risk of treatment failure.[60-63] The KMT2A::AFF1 fusion (t(4;11)(q21;q23)) is the most common rearrangement involving the KMT2A gene in children with ALL and occurs in approximately 1% to 2% of childhood ALL.[61,64]
     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.[65] While both infants and adults with the KMT2A::AFF1 fusion are at high risk of treatment failure, children with the KMT2A::AFF1 fusion appear to have a better outcome.[60,61,66] Irrespective of the type of KMT2A gene rearrangement, infants with leukemia cells that have KMT2A gene rearrangements have a worse treatment outcome than older patients whose leukemia cells have a KMT2A gene rearrangement.[60,61]
     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.[10] Deletion of the KMT2A gene has not been associated with an adverse prognosis.[67]
     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.[68] Outcome for infants with the KMT2A::MLLT1 fusion is poor, but outcome appears relatively favorable in older children with T-ALL and the KMT2A::MLLT1 fusion.[68]
   • TCF3::PBX1 fusion (t(1;19)(q23;p13.3)) and TCF3::HLF fusion (t(17;19)(q22;p13)).
     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.[1,69,70] The TCF3::PBX1 fusion may occur as either a balanced translocation or as an unbalanced translocation and is the primary recurring genomic alteration of the pre-B–ALL immunophenotype (cytoplasmic immunoglobulin positive).[71] Black children are relatively more likely than White children to have pre-B–ALL with the TCF3::PBX1 fusion.[72]
     The TCF3::PBX1 fusion had been associated with inferior outcome in the context of antimetabolite-based therapy,[73] but the adverse prognostic significance was largely negated by more aggressive multiagent therapies.[70,74] More specifically, in a trial conducted by St. Jude Children's Research Hospital (SJCRH) in which all patients were treated without cranial radiation, patients with the TCF3::PBX1 fusion had an overall outcome comparable to children lacking this translocation, but with a higher risk of CNS relapse and a lower rate of bone marrow relapse, suggesting that more intensive CNS therapy may be needed for these patients.[75,76]
     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.[77] In addition to the TCF3::HLF fusion, the genomic landscape of this ALL subtype was characterized by deletions in genes involved in B-cell development (PAX5, BTG1, and VPREB1) and by mutations in RAS pathway genes (NRAS, KRAS, and PTPN11).[71]
   • DUX4-rearranged ALL with frequent ERG deletions.
     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.[1,5,6] East Asian ancestry was linked to an increased prevalence of DUX4-rearranged ALL (favorable).[78] The most common rearrangement produces IGH::DUX4 fusions, with ERG::DUX4 fusions also observed.[79] DUX4-rearranged cases show a distinctive gene expression pattern that was initially identified as being associated with focal deletions in ERG,[79-82] and one-half to more than two-thirds of these cases have focal intragenic deletions involving ERG that are not observed in other ALL subtypes.[5,79] ERG deletions often appear to be clonal, but using sensitive detection methodology, it appears that most cases are polyclonal.[79] IKZF1 alterations are observed in 20% to 40% of DUX4-rearranged ALL.[5,6]
     ERG deletion connotes an excellent prognosis, with OS rates exceeding 90%. Even when the IZKF1 deletion is present, prognosis remains highly favorable.[80-83] While patients with DUX4-rearranged ALL have an overall favorable prognosis, there is uncertainty as to whether this applies to both ERG-deleted and ERG-intact cases. In a study of 50 patients with DUX4-rearranged ALL, patients with an ERG deletion detected by genomic polymerase chain reaction (PCR) (n = 33) had a more favorable EFS rate of approximately 90% than did patients with intact ERG (n = 17), with an EFS rate of approximately 70%.[81]
   • MEF2D-rearranged ALL.
     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.[1,84,85]
     Although multiple fusion partners may occur, most cases involve BCL9, which is located on chromosome 1q21, as is MEF2D.[84,86] The interstitial deletion producing the MEF2D::BCL9 fusion is too small to be detected by conventional cytogenetic methods. Cases with MEF2D gene fusions show a distinctive gene expression profile, except for rare cases with MEF2D::CSFR1 that have a BCR::ABL1-like gene expression profile.[84,87]
     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.[84,85] For 22 children with MEF2D-rearranged ALL enrolled in a high-risk ALL clinical trial, the 5-year EFS rate was 72% (standard error, ± 10%), which was inferior to that for other patients.[84]
   • ZNF384-rearranged ALL.
     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.[1,84,88,89]
     East Asian ancestry was associated with an increased prevalence of ZNF384.[78] Multiple fusion partners for ZNF384 have been reported, including ARID1B, CREBBP, EP300, SMARCA2, TAF15, and TCF3. Regardless of the fusion partner, ZNF384-rearranged ALL cases show a distinctive gene expression profile.[84,88,89] ZNF384 rearrangement does not appear to confer independent prognostic significance.[84,88,89] However, within the subset of patients with ZNF384 rearrangements, patients with EP300::ZNF384 fusions have lower relapse rates than patients with other ZNF384 fusion partners.[90] The immunophenotype of B-ALL with ZNF384 rearrangement is characterized by weak or negative CD10 expression, with expression of CD13 and/or CD33 commonly observed.[88,89] Cases of mixed phenotype acute leukemia (MPAL) (B/myeloid) that have ZNF384 gene fusions have been reported,[91,92] and a genomic evaluation of MPAL found that ZNF384 gene fusions were present in approximately one-half of B/myeloid cases.[93]
   • NUTM1-rearranged B-ALL.
     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.[94] The frequency of NUTM1 rearrangement is lower in children after infancy (<1% of cases).[1,94]
     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.[95] RNA sequencing, as well as break-apart FISH, can be used to detect the presence of the NUTM1 rearrangement.[94]
     The NUTM1 rearrangement appears to be associated with a favorable outcome.[94,96] Among 35 infants with NUTM1-rearranged B-ALL who were treated on Interfant protocols, all patients achieved remission and no relapses were observed.[94] For the 32 children older than 12 months with NUTM1-rearranged B-ALL, the 4-year EFS and OS rates were 92% and 100%, respectively.
   • IGH::IL3 fusion (t(5;14)(q31.1;q32.3)).
     This entity is included in the 2016 revision of the World Health Organization (WHO) classification of tumors of the hematopoietic and lymphoid tissues.[97] The finding of t(5;14)(q31.1;q32.3) in patients with ALL and hypereosinophilia in the 1980s was followed by the identification of the IGH::IL3 fusion as the underlying genetic basis for the condition.[98,99] The joining of the IGH locus to the promoter region of the IL3 gene leads to dysregulation of IL3 expression.[100] Cytogenetic abnormalities in children with ALL and eosinophilia are variable, with only a subset resulting from the IGH::IL3 fusion.[101]
     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.[97]
   • Intrachromosomal amplification of chromosome 21 (iAMP21).
     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).[97] It occurs in approximately 5% of NCI standard-risk and 7% of NCI high-risk pediatric B-ALL cases.[1]
     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.[102-104] Analysis of mutational signatures indicates that gene amplifications in iAMP21 occur later in leukemogenesis, which is in contrast to those of hyperdiploid ALL that can arise early in life and even in utero.[1]
     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%).[16] In their subsequent trial (UKALL2003 [NCT00222612]), patients with iAMP21 were assigned to a more intensive chemotherapy regimen and had a markedly better outcome (5-year EFS rate, 78%).[103] Similarly, the COG has reported that iAMP21 was associated with a significantly inferior outcome in NCI standard-risk patients (4-year EFS rate, 73% for iAMP21 vs. 92% in others), but not in NCI high-risk patients (4-year EFS rate, 73% vs. 80%).[102] On multivariate analysis, iAMP21 was an independent predictor of inferior outcome only in NCI standard-risk patients.[102] The results of the UKALL2003 and COG studies suggest that treatment of iAMP21 patients with high-risk chemotherapy regimens abrogates its adverse prognostic significance and obviates the need for HSCT in first remission.[104]
   • PAX5 alterations.
     Gene expression analysis identified two distinctive ALL subsets with PAX5 genomic alterations, called PAX5alt and PAX5 p.P80R (NP_057953.1).[105] The alterations in the PAX5alt subtype included rearrangements, sequence mutations, and focal intragenic amplifications.
     PAX5alt. PAX5 rearrangements have been reported to represent approximately 3% of NCI standard-risk and 11% of NCI high-risk pediatric B-ALL cases.[1] More than 20 partner genes for PAX5 have been described,[105] with PAX5::ETV6, the primary genomic alteration in dic(9;12)(p13;p13),[106] being the most common gene fusion.[105]
     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.[107] Cases with PAX5 amplification show male predominance (66%), with most (55%) having NCI high-risk status. For a cohort of patients with PAX5 amplification diagnosed between 1993 and 2015, the 5-year EFS rate was 49% (95% confidence interval [CI], 36%–61%), and the OS rate was 67% (95% CI, 54%–77%), suggesting a relatively poor prognosis for patients with this B-ALL subtype.
     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.[105] Cases with PAX5 p.P80R represent approximately 0.3% of NCI standard-risk and 1.8% of NCI high-risk pediatric B-ALL.[1] PAX5 p.P80R B-ALL appears to occur more frequently in the adolescent and young adult (AYA) and adult populations (3.1% and 4.2%, respectively).[105]
     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%).[105] PAX5alt rearrangements have also been detected in infant patients with ALL, with a reported outcome similar to KMT2A-rearranged infant ALL.[96]
   • BCR::ABL1-like (Ph-like).
     BCR::ABL1-negative patients with a gene expression profile similar to BCR::ABL1-positive patients have been referred to as Ph-like,[108-110] and are now referred to as BCR::ABL1-like.[17] This occurs in 10% to 20% of pediatric B-ALL patients, increasing in frequency with age, and has been associated with an IKZF1 deletion or mutation.[1,8,108,109,111,112]
     Retrospective analyses have indicated that patients with BCR::ABL1-like ALL have a poor prognosis.[4,108] In one series, the 5-year EFS rate for NCI high-risk children and adolescents with BCR::ABL1-like ALL was 58% and 41%, respectively.[4] While it is more frequent in older and higher-risk patients, the BCR::ABL1-like subtype has also been identified in NCI standard-risk patients. In a COG study, 13.6% of 1,023 NCI standard-risk B-ALL patients were found to have BCR::ABL1-like ALL; these patients had an inferior EFS rate compared with non–BCR::ABL1-like standard-risk patients (82% vs. 91%), although no difference in OS rate (93% vs. 96%) was noted.[113] In one study of 40 BCR::ABL1-like patients, the adverse prognostic significance of this subtype appeared to be abrogated when patients were treated with risk-directed therapy on the basis of MRD levels.[114]
     The hallmark of BCR::ABL1-like ALL is activated kinase signaling, with approximately 35% to 50% containing CRLF2 genomic alterations [1,110,115] and half of those cases containing concomitant JAK mutations.[116]
     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.[4,111,117] Fusion proteins from these gene combinations have been noted in some cases to be transformative and have responded to tyrosine kinase inhibitors both in vitro and in vivo,[111] suggesting potential therapeutic strategies for these patients.
     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.[1] In a retrospective study of 122 pediatric patients (aged 1–18 years) with ABL-class fusions (all treated without tyrosine kinase inhibitors), the 5-year EFS rate was 59%, and the OS rate was 76%.[118]
     Approximately 9% of BCR::ABL1-like ALL cases result from rearrangements that lead to overexpression of a truncated erythropoietin receptor (EPOR).[119] The C-terminal region of the receptor that is lost is the region that is mutated in primary familial congenital polycythemia and that controls stability of the EPOR. The portion of the EPOR remaining is sufficient for JAK-STAT activation and for driving leukemia development. Point mutations in kinase genes, aside from those in JAK1 and JAK2, are uncommon in patients with BCR::ABL1-like ALL.[8]
     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.[120-122] The chromosomal abnormalities that commonly lead to CRLF2 overexpression include translocations of the IGH locus (chromosome 14) to CRLF2 and interstitial deletions in pseudoautosomal regions of the sex chromosomes, resulting in a P2RY8::CRLF2 fusion.[8,115,120,121] These two genomic alterations are associated with distinctive clinical and biological characteristics.
     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.[1]
     ALL with genomic alterations in CRLF2 occurs at a higher incidence in children with Hispanic or Latino genetic ancestry [115,123] and American Indian genetic ancestry.[78] In a study of 205 children with high-risk B-ALL, 18 of 51 (35.3%) Hispanic or Latino patients had CRLF2 rearrangements, compared with 11 of 154 (7.1%) cases of other declared ethnicity.[115] In a second study, only the frequency of IGH::CRLF2 fusions was increased in Hispanic or Latino children compared with non-Hispanic or non-Latino children with B-ALL (12% vs. 2.7%).[123] In this study, the percentage of B-ALL with P2RY8::CRLF2 fusions was approximately 6% and was not affected by ethnicity.
     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).[124,125] P2RY8::CRLF2 occurs not infrequently with established chromosomal abnormalities (e.g., hyperdiploidy, iAMP21, dic(9;20)), while IGH::CRLF2 is generally mutually exclusive with known cytogenetic subgroups. CRLF2 genomic alterations are observed in approximately 60% of patients with Down syndrome and ALL, with P2RY8::CRLF2 fusions being more common than IGH::CRLF2 (approximately 80% vs. 20%).[121,124]
     IGH::CRLF2 and P2RY8::CRLF2 commonly occur as an early event in B-ALL development and show clonal prevalence.[126] However, in some cases they appear to be a late event and show subclonal prevalence.[126] Loss of the CRLF2 genomic abnormality in some cases at relapse confirms the subclonal nature of the alteration in these cases.[124,127]
     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.[125] Other recurring genomic alterations found in association with CRLF2 alterations include deletions in genes associated with B-cell differentiation (e.g., PAX5, BTG1, EBF1, etc.) and cell cycle control (CDKN2A), as well as genomic alterations activating JAK-STAT pathway signaling (e.g., IL7R and JAK mutations).[4,115,116,121,128]
     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.[115,120,121,129,130] For example, in a large European study, increased expression of CRLF2 was not associated with unfavorable outcome in multivariate analysis, while IKZF1 deletion and BCR::ABL1-like expression signatures were associated with unfavorable outcome.[112] Controversy exists about whether the prognostic significance of CRLF2 abnormalities should be analyzed on the basis of CRLF2 overexpression or on the presence of CRLF2 genomic alterations.[129,130]
   • IKZF1 deletions.
     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.[109]
     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.[2,109,128,131] A high proportion of BCR::ABL1-positive cases have a deletion of IKZF1,[3,128] and ALL arising in children with Down syndrome appears to have elevated rates of IKZF1 deletions.[132] IKZF1 deletions are also common in cases with CRLF2 genomic alterations and in BCR::ABL1-like ALL cases.[80,108,128]
     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.[80,108,109,112,128,133-139]; [140][Level of evidence B4] However, the prognostic significance of IKZF1 may not apply equally across ALL biological subtypes, as illustrated by the apparent lack of prognostic significance in patients with ERG deletions.[80-82] Similarly, the prognostic significance of the IKZF1 deletion also appeared to be minimized in a cohort of COG patients with DUX4-rearranged ALL and with ERG transcriptional dysregulation that frequently occurred by ERG deletion.[6] The Associazione Italiana di Ematologia e Oncologia Pediatrica–Berlin-Frankfurt-Münster group reported that IKZF1 deletions were significant adverse prognostic factors only in B-ALL patients with high end-induction MRD and in whom co-occurrence of deletions of CDKN2A, CDKN2B, PAX5, or PAR1 (in the absence of ERG deletion) were identified.[141] The poor prognosis associated with IKZF1 alterations appears to be enhanced by the concomitant finding of deletion of 22q11.22. In a study of 1,310 patients with B-ALL, approximately one-half of the patients with IKZF1 alterations also had deletion of 22q11.22. The 5-year EFS rate was 43.3% for those with both abnormalities, compared with 68.5% for patients with IKZF1 alterations and wild-type 22q11.22 (P < .001).[142]
     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.[143][Level of evidence B4]
   • MYC-rearranged ALL (8q24).
     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.[144-146] The lymphoblasts typically exhibit a precursor B-cell immunophenotype, with a French-American-British (FAB) L2 or L3 morphology, with no expression of surface immunoglobulin and kappa or lambda light chains. Concurrent MYC gene rearrangements have been observed along with additional cytogenetic rearrangements such as IGH::BCL2 or KMT2A.[146] Patients reported in the literature have been variably treated with ALL therapy or with mature B leukemia/lymphoma treatment protocols, and the optimal treatment for this patient group remains uncertain.[146]

T-ALL cytogenetics/genomics

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.[147] Cytogenetic abnormalities common in B-ALL (e.g., hyperdiploidy, 51–65 chromosomes) are rare in T-ALL.[148,149]

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.[1] Each subtype is associated with dysregulation of specific genes involved in T-cell development. Within a subtype, multiple mechanisms may drive expression of the dysregulated gene. For example, for the largest subtype, TAL1, overexpression of TAL1 can result from the STIL::TAL1 fusion and a noncoding insertion mutation upstream of the TAL1 locus that creates a MYB-binding site.[147,150] As another example, within the HOXA group, overexpression of HOXA9 can result from multiple gene fusions, including KMT2A rearrangements, MLLT10 rearrangements, and SET::NUP214 fusions.[1,147,151] In contrast to the molecular subtypes of B-ALL, the molecular subtypes of T-ALL are not used to define treatment interventions based on their prognostic significance or therapeutic implications.

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.
  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.[147,152] NOTCH1-activating gene mutations occur in approximately 50% to 60% of T-ALL cases, and FBXW7-inactivating gene mutations occur in approximately 15% of cases. Approximately 60% of T-ALL cases have Notch pathway activation by mutations in at least one of these genes.[153,154]
  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).[155,156] In the FRALLE study, the 5-year disease-free survival rate was 88% for the genetic low-risk group of patients and 60% for the genetic high-risk group of patients.[155] However, using the same criteria to define the genetic risk group, the Dana-Farber Cancer Institute consortium was unable to replicate these results. They reported a 5-year EFS rate of 86% for genetic low-risk patients and 79% for the genetic high-risk patients, a difference that was not statistically significant (P = .26).[154]
• Chromosomal translocations.
  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.[147,148,157-161] These translocations are often not apparent by examining a standard karyotype, but can be identified using more sensitive screening techniques, including FISH or PCR.[148] Mutations in a noncoding region near the TAL1 gene that produce a super-enhancer upstream of TAL1 represent nontranslocation genomic alterations that can also activate TAL1 transcription to induce T-ALL.[150]
  Translocations resulting in chimeric fusion proteins are also observed in T-ALL.[155]

  • A NUP214::ABL1 fusion has been noted in 4% to 6% of T-ALL cases and is observed in both adults and children, with a male predominance.[162-164] The fusion is cytogenetically cryptic and is seen in FISH on amplified episomes or, more rarely, as a small homogeneous staining region.[164] T-ALL may also uncommonly show ABL1 fusion proteins with other gene partners (e.g., ETV6, BCR, and EML1).[164] ABL tyrosine kinase inhibitors, such as imatinib or dasatinib, may demonstrate therapeutic benefits in this T-ALL subtype,[162,163,165] although clinical experience with this strategy is very limited.[166-168]
  • Gene fusions involving SPI1 (encoding the transcription factor PU.1) were reported in 4% of Japanese children with T-ALL.[169] Fusion partners included STMN1 and TCF7. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.
  • Other recurring gene fusions in T-ALL patients include those involving MLLT10, KMT2A, NUP214, and NUP98.[147,151]

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.[170] Compared with other T-ALL cases, the early T-cell precursor group had a lower rate of NOTCH1 mutations and significantly higher frequencies of alterations in genes regulating cytokine receptors and RAS signaling, hematopoietic development, and histone modification. The transcriptional profile of early T-cell precursor ALL shows similarities to that of normal hematopoietic stem cells and myeloid leukemia stem cells.[170]

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.[171,172] ABD is characteristic of early thymic precursor cells, and many of the T-ALL patients with ABD have an immunophenotype consistent with the diagnosis of early T-cell precursor phenotype.

Acute Myeloid Leukemia (AML)

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.[347-349] In a series of 118 consecutively diagnosed JMML cases with RAS pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (see Figure 5).[347] Patients with mutated NRAS accounted for 19% of cases, and patients with mutated KRAS accounted for 15% of cases. NF1 mutations accounted for 8% of cases, and CBL mutations accounted for 11% of cases. Although mutations among these five genes are generally mutually exclusive, 4% to 17% of cases have mutations in two of these RAS pathway genes,[347-349] a finding that is associated with poorer prognosis.[347,349]

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.[347-349] Secondary genomic alterations are observed for genes of the transcriptional repressor complex PRC2 (e.g., ASXL1 was mutated in 7%–8% of cases). Some genes associated with myeloproliferative neoplasms in adults are also mutated at low rates in JMML (e.g., SETBP1 was mutated in 6%–9% of cases).[347-350] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[347-350] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (see Figure 5).[347] The presence of mutations beyond disease-defining RAS pathway mutations is associated with an inferior prognosis.[347,348]

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.[349]

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

Myelodysplastic Syndromes (MDS)

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361. Narumi S, Amano N, Ishii T, et al.: SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7. Nat Genet 48 (7): 792-7, 2016. [PubMed: 27182967]
362. Chen DH, Below JE, Shimamura A, et al.: Ataxia-Pancytopenia Syndrome Is Caused by Missense Mutations in SAMD9L. Am J Hum Genet 98 (6): 1146-1158, 2016. [PMC free article: PMC4908176] [PubMed: 27259050]
363. Wong JC, Bryant V, Lamprecht T, et al.: Germline SAMD9 and SAMD9L mutations are associated with extensive genetic evolution and diverse hematologic outcomes. JCI Insight 3 (14): , 2018. [PMC free article: PMC6124395] [PubMed: 30046003]

Mature B-cell Lymphoma

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

Lymphoblastic Lymphoma

Anaplastic Large Cell Lymphoma

Pediatric-type Follicular Lymphoma

References

1. Leoncini L, Raphael M, Stein H, et al.: Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 330-4.
2. Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PubMed: 8606720]
3. Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003. [PubMed: 16224429]
4. Miles RR, Cairo MS, Satwani P, et al.: Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report. Br J Haematol 138 (4): 506-12, 2007. [PubMed: 17659054]
5. Gualco G, Weiss LM, Harrington WJ, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009. [PMC free article: PMC2788112] [PubMed: 19816150]
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9. Richter J, Schlesner M, Hoffmann S, et al.: Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44 (12): 1316-20, 2012. [PubMed: 23143595]
10. Havelange V, Pepermans X, Ameye G, et al.: Genetic differences between paediatric and adult Burkitt lymphomas. Br J Haematol 173 (1): 137-44, 2016. [PubMed: 26887776]
11. Rohde M, Bonn BR, Zimmermann M, et al.: Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols. Haematologica 102 (6): 1091-1098, 2017. [PMC free article: PMC5451341] [PubMed: 28209658]
12. Chakraborty AA, Scuoppo C, Dey S, et al.: A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34 (18): 2406-9, 2015. [PMC free article: PMC4286529] [PubMed: 24998853]
13. Masqué-Soler N, Szczepanowski M, Kohler CW, et al.: Clinical and pathological features of Burkitt lymphoma showing expression of BCL2--an analysis including gene expression in formalin-fixed paraffin-embedded tissue. Br J Haematol 171 (4): 501-8, 2015. [PubMed: 26218299]
14. Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 314-6.
15. Wagener R, Seufert J, Raimondi F, et al.: The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 133 (9): 962-966, 2019. [PMC free article: PMC6396176] [PubMed: 30567752]
16. Gonzalez-Farre B, Ramis-Zaldivar JE, Salmeron-Villalobos J, et al.: Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma. Haematologica 104 (9): 1822-1829, 2019. [PMC free article: PMC6717587] [PubMed: 30733272]
17. Au-Yeung RKH, Arias Padilla L, Zimmermann M, et al.: Experience with provisional WHO-entities large B-cell lymphoma with IRF4-rearrangement and Burkitt-like lymphoma with 11q aberration in paediatric patients of the NHL-BFM group. Br J Haematol 190 (5): 753-763, 2020. [PubMed: 32239695]
18. Gascoyne RD, Campo E, Jaffe ES, et al.: Diffuse large B-cell lymphoma, NOS. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 291-7.
19. Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006. [PubMed: 16424389]
20. Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008. [PMC free article: PMC2712231] [PubMed: 18493992]
21. Ramis-Zaldivar JE, Gonzalez-Farré B, Balagué O, et al.: Distinct molecular profile of IRF4-rearranged large B-cell lymphoma. Blood 135 (4): 274-286, 2020. [PMC free article: PMC6978155] [PubMed: 31738823]
22. Klapper W, Kreuz M, Kohler CW, et al.: Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 119 (8): 1882-7, 2012. [PubMed: 22238326]
23. Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008. [PubMed: 18509088]
24. Deffenbacher KE, Iqbal J, Sanger W, et al.: Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 119 (16): 3757-66, 2012. [PMC free article: PMC3335381] [PubMed: 22374697]
25. Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009. [PMC free article: PMC2988438] [PubMed: 19020548]
26. Pittaluga S, Harris NL, Siebert R, et al.: Large B-cell lymphoma with IRF4 rearrangement. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 280-1.
27. Chisholm KM, Mohlman J, Liew M, et al.: IRF4 translocation status in pediatric follicular and diffuse large B-cell lymphoma patients enrolled in Children's Oncology Group trials. Pediatr Blood Cancer 66 (8): e27770, 2019. [PMC free article: PMC6941672] [PubMed: 31012208]
28. Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011. [PubMed: 21487109]
29. Liu Q, Salaverria I, Pittaluga S, et al.: Follicular lymphomas in children and young adults: a comparison of the pediatric variant with usual follicular lymphoma. Am J Surg Pathol 37 (3): 333-43, 2013. [PMC free article: PMC3566339] [PubMed: 23108024]
30. Kluin PM, Harris NL, Stein H, et al.: High-grade B-cell lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 335-41.
31. Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. International Agency for Research on Cancer, 2008, pp 157-66.
32. Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003. [PMC free article: PMC2194208] [PubMed: 12975453]
33. Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003. [PubMed: 12933571]
34. Mottok A, Hung SS, Chavez EA, et al.: Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma. Blood 134 (10): 802-813, 2019. [PubMed: 31292115]
35. Green MR, Monti S, Rodig SJ, et al.: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116 (17): 3268-77, 2010. [PMC free article: PMC2995356] [PubMed: 20628145]
36. Twa DD, Chan FC, Ben-Neriah S, et al.: Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123 (13): 2062-5, 2014. [PubMed: 24497532]
37. Chong LC, Twa DD, Mottok A, et al.: Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 128 (9): 1206-13, 2016. [PubMed: 27268263]
38. Chapuy B, Stewart C, Dunford AJ, et al.: Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade. Blood 134 (26): 2369-2382, 2019. [PMC free article: PMC6933293] [PubMed: 31697821]
39. Mottok A, Woolcock B, Chan FC, et al.: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep 13 (7): 1418-1431, 2015. [PubMed: 26549456]
40. Viganò E, Gunawardana J, Mottok A, et al.: Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation. Blood 131 (18): 2036-2046, 2018. [PubMed: 29467182]
41. Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005. [PMC free article: PMC1895326] [PubMed: 16046532]
42. Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011. [PMC free article: PMC3031694] [PubMed: 20971819]
43. Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005. [PubMed: 15572583]
44. Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005. [PubMed: 15815722]
45. Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000. [PubMed: 10881003]
46. Liu Y, Easton J, Shao Y, et al.: The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet 49 (8): 1211-1218, 2017. [PMC free article: PMC5535770] [PubMed: 28671688]
47. Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013. [PubMed: 23396305]
48. Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008. [PubMed: 18297521]
49. Balbach ST, Makarova O, Bonn BR, et al.: Proposal of a genetic classifier for risk group stratification in pediatric T-cell lymphoblastic lymphoma reveals differences from adult T-cell lymphoblastic leukemia. Leukemia 30 (4): 970-3, 2016. [PubMed: 26216196]
50. Khanam T, Sandmann S, Seggewiss J, et al.: Integrative genomic analysis of pediatric T-cell lymphoblastic lymphoma reveals candidates of clinical significance. Blood 137 (17): 2347-2359, 2021. [PMC free article: PMC8759350] [PubMed: 33152759]
51. Callens C, Baleydier F, Lengline E, et al.: Clinical impact of NOTCH1 and/or FBXW7 mutations, FLASH deletion, and TCR status in pediatric T-cell lymphoblastic lymphoma. J Clin Oncol 30 (16): 1966-73, 2012. [PubMed: 22547598]
52. Meyer JA, Zhou D, Mason CC, et al.: Genomic characterization of pediatric B-lymphoblastic lymphoma and B-lymphoblastic leukemia using formalin-fixed tissues. Pediatr Blood Cancer 64 (7): , 2017. [PubMed: 27957801]
53. Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127 (20): 2375-90, 2016. [PMC free article: PMC4874220] [PubMed: 26980727]
54. Duyster J, Bai RY, Morris SW: Translocations involving anaplastic lymphoma kinase (ALK). Oncogene 20 (40): 5623-37, 2001. [PubMed: 11607814]
55. Tsuyama N, Sakamoto K, Sakata S, et al.: Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. J Clin Exp Hematop 57 (3): 120-142, 2017. [PMC free article: PMC6144189] [PubMed: 29279550]
56. Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008. [PubMed: 18385450]
57. Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008. [PubMed: 18626005]
58. Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PubMed: 11090048]
59. Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PubMed: 22084369]
60. Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PMC free article: PMC4682366] [PubMed: 25156886]
61. Jaffe ES, Harris NL, Siebert R: Paediatric-type follicular lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. International Agency for Research on Cancer, 2017, pp 278-9.
62. Launay E, Pangault C, Bertrand P, et al.: High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 26 (3): 559-62, 2012. [PubMed: 21941365]
63. Schmidt J, Gong S, Marafioti T, et al.: Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 128 (8): 1101-11, 2016. [PMC free article: PMC5000845] [PubMed: 27257180]
64. Louissaint A, Schafernak KT, Geyer JT, et al.: Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood 128 (8): 1093-100, 2016. [PMC free article: PMC5000844] [PubMed: 27325104]
65. Schmidt J, Ramis-Zaldivar JE, Nadeu F, et al.: Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130 (3): 323-327, 2017. [PMC free article: PMC5520474] [PubMed: 28533310]
66. Ozawa MG, Bhaduri A, Chisholm KM, et al.: A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. Mod Pathol 29 (10): 1212-20, 2016. [PMC free article: PMC5047957] [PubMed: 27338637]

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.[1,2] Characterization of genomic alterations for Hodgkin lymphoma is challenging because malignant Hodgkin and Reed-Sternberg (HRS) cells make up only a small percentage of the overall tumor mass. Because of this finding, special methods, such as microdissection of HRS cells or flow cytometry cell sorting, are required before applying molecular analysis methods.[2,3] Hodgkin lymphoma genomic alterations can also be assessed using special sequencing methods applied to circulating cell-free DNA (cfDNA) in peripheral blood of patients with Hodgkin lymphoma.[4]

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:

• Multiple genomic alterations contribute to immune evasion in Hodgkin lymphoma.

  • Copy number gain or amplification at chromosome 9p24 is observed in most cases of Hodgkin lymphoma.[5,6] This region encodes the immune checkpoint genes CD274 (encoding PD-L1) and PDCD1LG2 (encoding PD-L2). These genomic alterations lead to increased expression of these checkpoint proteins.[5,6]
  • Gene fusions involving CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, were reported in 15% of Hodgkin lymphoma cases.[7] Similar alterations are found in primary mediastinal B-cell lymphoma, and they lead to decreased CIITA protein expression and loss of MHC class II expression.[7,8]
  • Beta-2-microglobulin (the invariant chain of the MHC class I) frequently shows decreased/absent expression in HRS cells, with accompanying decreased MHC class I expression.[9] Inactivating mutations in B2M, the gene that encodes beta-2-microglobulin, are common in Hodgkin lymphoma and lead to reduced expression of MHC class I.[2,10] Inactivating mutations in B2M occur more frequently in Epstein-Barr virus (EBV)-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma,[2] which explains the higher rates of beta-2 microglobulin and MHC class I expression for EBV-positive Hodgkin lymphoma, compared with EBV-negative Hodgkin lymphoma.[9]
• Genomic alterations involving genes in the JAK-STAT pathway are observed in most cases of Hodgkin lymphoma.[3] Genes in the JAK-STAT pathway for which genomic alterations are reported include:

  • SOCS1, a negative regulator of JAK-STAT signaling, is inactivated by mutations in 60% to 70% of Hodgkin lymphoma cases.[3] In a study of pediatric Hodgkin lymphoma using cfDNA collected before treatment, SOCS1 was the most frequently mutated gene, with mutations in 60% of all cases and approximately 80% of cases in which genomic alterations were detected in cfDNA.[11]
  • Activating STAT6 mutations occurring at hot spots in the DNA-binding domain are observed in approximately 30% of Hodgkin lymphoma cases.[2,3]
  • The chromosome 9p region that contains CD274 and PDCD1LG2, which shows gains and amplifications in Hodgkin lymphoma, also contains JAK2.[2,3,12] Chromosome 9p gain/amplification is thought to further augment JAK-STAT pathway signaling.[12]
  • Inactivating mutations in PTPN1, a phosphatase that inhibits JAK-STAT pathway signaling, were observed in approximately 20% of Hodgkin lymphoma cases.[2,13]
  • Mutations in other genes affecting JAK-STAT pathway signaling have also been reported, including JAK1, STAT3, STAT5B, and CSF2RB.[2,3]
• Genomic alterations leading to NF-kappaB activation are also common in Hodgkin lymphoma.

  • The REL gene at chromosome 2p16.1 shows genomic gain or amplification in approximately one-third of Hodgkin lymphoma cases.[2,14]
  • EBV-positive Hodgkin lymphoma expresses the EBV latent membrane protein 1 (LMP1) at the cell surface. This protein acts like a constitutively activated receptor of the TNF receptor family to cause activation of the NF-kappaB pathway.[15]
  • Inactivating mutations in genes that inhibit NF-kappaB pathway signaling, including TNFAIP3, NFKBIA, and NFKBIE, are common in Hodgkin lymphoma. Inactivation of the gene products for these genes leads to NF-kappaB pathway activation. TNFAIP3 is the most commonly altered inhibitor of NF-kappaB pathway signaling, and loss of function alterations occur by either mutations or by focal 6q23.3 or arm-level 6q loss.[2,16] TNFAIP3 genomic alterations are much more common in EBV-negative Hodgkin lymphoma than in EBV-positive Hodgkin lymphoma, suggesting that LMP1 expression in EBV-positive Hodgkin lymphoma obviates the need for TNFAIP3 loss of function.[2,16]
• Other genes that are mutated in Hodgkin lymphoma include XPO1, RBM38, ACTB, ARID1A, and GNA13.[2-4]
• Hodgkin lymphoma is derived from a B-cell progenitor, and HRS cells generally do not express B-cell surface antigens. HRS cells do have immunoglobulin (Ig) heavy and light chain V gene rearrangements typical of B cells.[17,18] Although Ig genes have undergone rearrangements in HRS cells, the rearrangements are nonproductive and B-cell receptor is not expressed.

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.

• LP cells express B-cell antigens (e.g., CD19, CD20, CD22, and CD79A) and B-cell transcription factors (e.g., OCT2 and BOB1).[19,20]
• The expression of Bcl-6 and the presence of somatic hypermutations in the variable region of rearranged Ig heavy chain genes point to a germinal center derivation for LP cells.[21,22]
• IgD expression connotes a distinct type of nodular lymphocyte-predominant Hodgkin lymphoma that is associated with a very high male-to-female ratio (>10:1).[23,24] An evaluation of the antigenic specificity of the B-cell receptor in cases of IgD-positive nodular lymphocyte-predominant Hodgkin lymphoma found that in 7 of 8 cases (6 of 8 patients aged ≤18 years) the B-cell receptor recognized the DNA-directed RNA polymerase (RpoC) from Moraxella catarrhalis.[25] High-titer, light-chain-restricted anti-RpoC IgG1 serum-antibodies were observed in these patients. In addition, MID/hag is a superantigen expressed by M. catarrhalis that binds to the Fc domain of IgD and activates IgD-positive B cells. These observations support a role for M. catarrhalis in the development and maintenance of IgD-positive nodular lymphocyte-predominant Hodgkin lymphoma.
• Genomic analysis of nodular lymphocyte-predominant Hodgkin lymphoma is limited to a small number of patients using gene panels to evaluate microdissected specimens containing LP cells. Recurring mutated genes include SOCS1 (an inhibitor of JAK-STAT pathway signaling), DUSP2 (a dual specificity phosphatase that is a negative regulator of the MAP kinase pathway), JUNB (a transcription factor in the activator protein-1 family), and SGK1 (a serine-threonine kinase).[26-28]

For information about the treatment of childhood Hodgkin lymphoma, see Childhood Hodgkin Lymphoma Treatment.

References

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2. Wienand K, Chapuy B, Stewart C, et al.: Genomic analyses of flow-sorted Hodgkin Reed-Sternberg cells reveal complementary mechanisms of immune evasion. Blood Adv 3 (23): 4065-4080, 2019. [PMC free article: PMC6963251] [PubMed: 31816062]
3. Tiacci E, Ladewig E, Schiavoni G, et al.: Pervasive mutations of JAK-STAT pathway genes in classical Hodgkin lymphoma. Blood 131 (22): 2454-2465, 2018. [PMC free article: PMC6634958] [PubMed: 29650799]
4. Spina V, Bruscaggin A, Cuccaro A, et al.: Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma. Blood 131 (22): 2413-2425, 2018. [PubMed: 29449275]
5. Roemer MG, Advani RH, Ligon AH, et al.: PD-L1 and PD-L2 Genetic Alterations Define Classical Hodgkin Lymphoma and Predict Outcome. J Clin Oncol 34 (23): 2690-7, 2016. [PMC free article: PMC5019753] [PubMed: 27069084]
6. Roemer MGM, Redd RA, Cader FZ, et al.: Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma. J Clin Oncol 36 (10): 942-950, 2018. [PMC free article: PMC5877802] [PubMed: 29394125]
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8. Mottok A, Woolcock B, Chan FC, et al.: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep 13 (7): 1418-1431, 2015. [PubMed: 26549456]
9. Roemer MG, Advani RH, Redd RA, et al.: Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status. Cancer Immunol Res 4 (11): 910-916, 2016. [PMC free article: PMC5210180] [PubMed: 27737878]
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Pilocytic Astrocytomas and Other Astrocytic Tumors

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]).

Neuronal and Mixed Neuronal-Glial Tumors

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.

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

Medulloblastomas

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.[1] This change resulted from the recognition that many tumors previously classified as CNS PNETs have the common finding of amplification of the C19MC region on chromosome 19. These entities included ependymoblastoma, embryonal tumors with abundant neuropil and true rosettes (ETANTR), and some cases of medulloepithelioma. The 2016 WHO classification now categorizes tumors with C19MC amplification as embryonal tumor with multilayered rosettes (ETMR), C19MC-altered. Tumors previously classified as CNS PNETs are now termed CNS embryonal tumor, NOS, with the recognition that tumors in this category will likely be classified by their defining genomic lesions in future editions of the WHO classification.

Pineoblastoma

Ependymomas

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).[182-185]

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]).[135]

• Infratentorial tumors.

  -

  Posterior fossa ependymoma (PF-EPN).

  -

  Posterior fossa A (PF-EPN-A), loss of H3 K27 trimethylation mark.

  -

  Posterior fossa B (PF-EPN-B), retained H3 K27 trimethylation mark.

• Supratentorial tumors.

  -

  Supratentorial ependymoma (ST-EPN).

  -

  ZFTA fusion–positive ependymoma (ST-EPN-ZFTA). This was previously called RELA fusion–positive ependymoma (ST-EPN-RELA), but it was renamed because ZFTA is the new designation for C11orf95 and ZFTA may be fused with a partner gene other than RELA.[186]

  -

  YAP1 fusion–positive ependymoma (ST-EPN-YAP1).

• Spinal tumors.

  • Spinal ependymoma (SP-EPN).
  • Spinal ependymoma, MYCN-amplified (SP-EPN-MYCN).
  • Myxopapillary ependymoma (SP-EPN-MPE).

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.

Infratentorial tumors

Posterior fossa A ependymoma (PF-EPN-A)

The most common posterior fossa ependymoma subgroup is PF-EPN-A and is characterized by the following:

• Presentation in young children (median age, 3 years).[182,187]
• Low rates of mutations that affect protein structure, approximately five per genome.[183]
• Gain of chromosome 1q, a known poor prognostic factor for patients with ependymoma,[188] in approximately 25% of cases.[182,184,189]
• Loss of chromosome 6q, reported to be a poor prognostic factor for patients with PF-EPN-A, in 8% to 10% of cases.[190]
• A balanced chromosomal profile with few chromosomal gains or losses.[182,183]
• Loss of the H3 K27 trimethylation mark and globally hypomethylated DNA.[191] Loss of the H3 K27 trimethylation mark occurs by one of the following two mechanisms:

  • Recurrent mutations of EZHIP in 10% of cases, with high EZHIP mRNA expression across almost all PF-EPN-A.[192,193] EZHIP expression (with or without mutation) results in inhibition of the methyltransferase EZH2 leading to loss of the H3 K27 trimethylation mark.[193,194]
  • Recurrent K27M mutations in histone H3 variants in a small proportion of cases.[195,196] Unlike diffuse intrinsic pontine gliomas, mutations in H3.1 (HIST1H3B and HIST1H3C) are more common than mutations in H3.3 (H3F3A).[192] Histone mutations are mutually exclusive with high expression of EZHIP,[192] and they also lead to loss of the H3 K27 trimethylation mark though EZH2 inhibition.

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.[192] Gene expression profiling suggested that these two subtypes may arise in different anatomical locations in the hindbrain. Within both PFA-1 and PFA-2 groups, distinctive minor subtypes could be identified, suggesting the presence of heterogeneity. Additional study will be required to define the clinical significance of these subtypes.

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:

• Presentation primarily in adolescents and young adults (median age, 30 years).[182,187]
• Low rates of mutations that affect protein structure (approximately five per genome), with no recurring mutations.[184]
• Numerous cytogenetic abnormalities, primarily involving the gain/loss of whole chromosomes.[182,184]
• Retained H3 K27 trimethylation.[191]
• 1q gain and 6q loss occur in PF-EPN-B but have not been reported as prognostic in this subgroup (unlike PF-EPN-A).[197]

Supratentorial tumors

Supratentorial ependymomas with ZFTA fusions (ST-EPN-ZFTA)

ST-EPN-ZFTA is the largest subset of pediatric supratentorial ependymomas and is predominantly characterized by gene fusions involving RELA,[198,199] a transcriptional factor important in NF-κB pathway activity. ST-EPN-ZFTA is characterized by the following:

• Represents approximately 70% of supratentorial ependymomas in children,[198,199] and presents at a median age of 8 years.[182]
• Presence of ZFTA fusions result from chromothripsis involving chromosome 11q13.1.[198]
• Low rates of mutations that affect protein structure and near absence of recurring mutations outside of ZFTA-RELA fusions.[198]
• Evidence of NF-κB pathway activation at the protein and RNA level.[198]
• Gain of chromosome 1q, in approximately one-quarter of cases, with an indeterminate effect on survival.[182]
• The concordance was high between immunohistochemistry for nuclear p65-RelA, fluorescence in situ hybridization for ZFTA and RELA, and DNA methylation-based classification for defining ST-EPN-ZFTA.[200]
• Homozygous deletion of CDKN2A has been associated with a poor prognosis in patients with ZFTA fusion–positive ependymoma.[201][Level of evidence B4] CDKN2A deletion has also been reported as a secondary event in recurrent ependymoma.[202]

Supratentorial ependymomas with YAP1 fusions (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:

• Median age at diagnosis of 1.4 years.[182]
• Presence of a gene fusion involving YAP1, with MAMLD1 being the most common fusion partner.[182,198]
• A relatively stable genome with few chromosomal changes other than the YAP1 fusion.[182]

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.[30,203]

Spinal ependymoma with MYCN amplification (SP-EPN-MYCN)

SP-EPN-MYCN is rare, with only 27 cases reported.[204-207]

• Median age at presentation is 31 years (range, 12–56 years).
• High level of MYCN amplification is present at diagnosis and relapse.
• SP-EPN-MYCN has a unique methylation profile compared with other spinal cord ependymomas, MYCN-amplified pediatric-type glioblastoma, and neuroblastoma.

For information about the treatment of childhood ependymoma, see Childhood Ependymoma Treatment.

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Molecular features of hepatoblastoma

Genomic findings related to hepatoblastoma include the following:

• The frequency of mutations in hepatoblastoma, as determined by three groups using whole-exome sequencing, was very low (approximately three variants per tumor) in children younger than 5 years.[1-4] A pediatric pan-cancer genomics study found that hepatoblastoma had the lowest gene mutation rate among all childhood cancers studied.[5]
• Hepatoblastoma is primarily a disease of WNT pathway activation. The primary mechanism for WNT pathway activation is CTNNB1 activating mutations/deletions involving exon 3. CTNNB1 mutations have been reported in more than 80% of cases.[1,3,4,6,7] A less common cause of WNT pathway activation in hepatoblastoma is mutations in APC associated with familial adenomatosis polyposis coli.[6]
• NFE2L2 mutations were identified in 10 of 174 (6%), 4 of 88 (5%), and 5 of 112 (4%) cases of hepatoblastoma.[3,4,7] The presence of NFE2L2 mutations was associated with a lower survival rate.[7]
• Similar NFE2L2 mutations have been found in many types of cancer, including hepatocellular carcinoma. These mutations render NFE2L2 insensitive to KEAP1-mediated degradation, leading to activation of the NFE2L2-KEAP1 pathway, which activates resistance to oxidative stress and is believed to confer resistance to chemotherapy.
• TERT and TP53 mutations, which are common in adults with hepatocellular carcinoma,[8] are uncommon in pediatric hepatoblastoma.[1,3,4,6] Hepatoblastoma cases with TERT mutations occur at a significantly older age, compared with hepatoblastoma cases without TERT mutations (median age at diagnosis, approximately 10 years vs. 1.4 years).[7]
• Uniparental disomy at 11p15.5 with loss of the maternal allele was reported in 6 of 15 cases of hepatoblastoma.[9] This finding has been confirmed in genomic characterization studies, in which 30% to 40% of cases showed allelic imbalance at the 11p15 locus.[4,6,7]