Childhood Cancer Genomics (PDQ®) 2/8 —Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)—Health Professional Version - National Cancer Institute

Childhood Cancer Genomics (PDQ®)–Health Professional Version

Molecular abnormalities associated with an unfavorable prognosis

Molecular abnormalities associated with an unfavorable prognosis include the following:

• Chromosomes 5 and 7: Chromosomal abnormalities associated with poor prognosis in adults with AML include those involving chromosome 5 (monosomy 5 and del(5q)) and chromosome 7 (monosomy 7).[160,174,216] These cytogenetic subgroups represent approximately 2% and 4% of pediatric AML cases, respectively, and are also associated with poor prognosis in children.[163,174,216-220]
  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.[165] However, outcome for children with del(7q), but not monosomy 7, appears comparable to that of other children with AML.[164,219] The presence of del(7q) does not abrogate the prognostic significance of favorable cytogenetic characteristics (e.g., inv(16) and t(8;21)).[160,219,221]
  Chromosome 5 and 7 abnormalities appear to lack prognostic significance in AML patients with Down syndrome who are aged 4 years and younger.[222]
• AML with inv(3)(q21.3;q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM: MECOM at chromosome 3q26 codes for two proteins, EVI1 and MDS1-EVI1, both of which are transcription regulators. The inv(3) and t(3;3) abnormalities lead to overexpression of EVI1 and to reduced expression of GATA2.[223,224] These abnormalities are associated with poor prognosis in adults with AML,[160,174,225] but are very uncommon in children (<1% of pediatric AML cases).[163,176,226]
  Abnormalities involving MECOM can be detected in some AML cases with other 3q abnormalities and are also associated with poor prognosis.
• FLT3 mutations: Presence of a FLT3-ITD mutation appears to be associated with poor prognosis in adults with AML,[227] particularly when both alleles are mutated or there is a high ratio of the mutant allele to the normal allele.[228,229] FLT3-ITD mutations also convey a poor prognosis in children with AML.[169,201,230-233] The frequency of FLT3-ITD mutations in children is lower than that observed in adults, especially for children younger than 10 years, for whom 5% to 10% of cases have the mutation (compared with approximately 30% in adults).[232-234]
  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.[235,236] Approximately 15% of patients with FLT3-ITD have NUP98-NSD1, and patients with both FLT3-ITD and NUP98-NSD1 have a poorer prognosis than do patients who have FLT3-ITD without NUP98-NSD1.[236] For patients who have FLT3-ITD, the presence of either WT1 mutations or NUP98-NSD1 fusions is associated with poorer outcome (EFS rates below 25%) than for patients who have FLT3-ITDwithout these alterations.[158] Conversely, when FLT3-ITD is accompanied by NPM1mutations, the outcome is relatively favorable and is similar to that of pediatric AML cases without FLT3-ITD.[158]
  For APL, FLT3-ITD and point mutations occur in 30% to 40% of children and adults.[228,231,232,237-241] Presence of the FLT3-ITD mutation is strongly associated with the microgranular variant (M3v) of APL and with hyperleukocytosis.[231,239,242,243] It remains unclear whether FLT3 mutations are associated with poorer prognosis in patients with APL who are treated with modern therapy that includes all-trans retinoic acid and arsenic trioxide.[237,238,241,242,244-247]
  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.[158]
• AML with t(16;21)(p11;q22); FUS-ERG: In leukemias with t(16;21)(p11;q22), the FUSgene is joined with the ERG gene, producing a distinctive AML subtype with a gene expression profile that clusters separately from other cytogenetic subgroups.[182] These patients present at a median age of 8 to 9 years and are rare, representing approximately 0.3% to 0.5% of pediatric AML cases. For a cohort of 31 patients with FUS-ERG AML, outcome was poor, with a 4-year EFS of 7% and a cumulative incidence of relapse of 74%.[182]

Other molecular abnormalities observed in pediatric AML

Other molecular abnormalities observed in pediatric AML include the following:

• KMT2A (MLL) gene rearrangements: KMT2A gene rearrangement occurs in approximately 20% of children with AML.[163,164] These cases, including most AMLs secondary to epipodophyllotoxin,[248] are generally associated with monocytic differentiation (FAB M4 and M5). KMT2A rearrangements are also reported in approximately 10% of FAB M7 (AMKL) patients (see below).[213,249]
  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(AF9) gene.[250] The WHO 2016 revision defined AML with t(9;11)(p21.3;q23.3); MLLT3-KMT2A as a distinctive disease entity. However, more than 50 different fusion partners have been identified for the KMT2A gene in patients with AML.
  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.[250] However, significantly older median ages are seen at presentation of pediatric cases with t(6;11)(q27;q23) (12 years) and t(11;17)(q23;q21) (9 years).[250]
  Outcome for patients with de novo AML and KMT2A gene rearrangement is generally reported as being similar to that for other patients with AML.[160,163,250,251] However, as the KMT2A gene can participate in translocations with many different fusion partners, the specific fusion partner appears to influence prognosis, as demonstrated by a large international retrospective study evaluating outcome for 756 children with 11q23- or KMT2A-rearranged AML.[250] For example, cases with t(1;11)(q21;q23), representing 3% of all 11q23/KMT2A-rearranged AML, showed a highly favorable outcome, with a 5-year event-free survival (EFS) of 92%.
  While reports from single clinical trial groups have variably described more favorable prognosis for patients with AML who have t(9;11)(p21.3;q23.3)/MLLT3-KMT2A, the international retrospective study did not confirm the favorable prognosis for this subgroup.[160,163,250,252-254] An international collaboration evaluating pediatric AMKL patients observed that the presence of t(9;11), which was seen in approximately 5% of AMKL cases, was associated with an inferior outcome compared with other AMKL cases.[249]
  KMT2A-rearranged AML subgroups that appear to be associated with poor outcome include the following:
  • Cases with the t(10;11) translocation are a group at high risk of relapse in bone marrow and the CNS.[160,164,255] Some cases with the t(10;11) translocation have fusion of the KMT2A gene with the AF10-MLLT10 at 10p12, while others have fusion of KMT2A with ABI1 at 10p11.2.[256,257] An international retrospective study found that these cases, which present at a median age of approximately 1 year, have a 5-year EFS of 20% to 30%.[250]
  • Patients with t(6;11)(q27;q23) have a poor outcome, with a 5-year EFS of 11%.
  • Patients with t(4;11)(q21;q23) also have a poor outcome, with a 5-year EFS of 29%.[250]
  • A follow-up study by the international collaborative group demonstrated that additional cytogenetic abnormalities further influenced outcome of children with KMT2A translocations, with complex karyotypes and trisomy 19 predicting poor outcome and trisomy 8 predicting a more favorable outcome.[258]
• AML with t(6;9)(p23;q34.1); DEK-NUP214: t(6;9) leads to the formation of a leukemia-associated fusion protein DEK-NUP214.[259,260] This subgroup of AML has been associated with a poor prognosis in adults with AML,[259,261,262] and occurs infrequently in children (less than 1% of AML cases). The median age of children with DEK-NUP214 AML is 10 to 11 years, and approximately 40% of pediatric patients have FLT3-ITD.[263,264]
  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.[163,260,263,264]
• Molecular subgroups of non–Down syndrome acute megakaryoblastic leukemia (AMKL): AMKL accounts for approximately 10% of pediatric AML and includes substantial heterogeneity at the molecular level. Molecular subtypes of AMKL are listed below.
  • CBFA2T3-GLIS2: CBFA2T3-GLIS2 is a fusion resulting from a cryptic chromosome 16 inversion (inv(16)(p13.3q24.3)).[265-269] It occurs almost exclusively in non–Down syndrome AMKL, representing 16% to 27% of pediatric AMKL and presenting with a median age of 1 year.[213,267,270,271] It appears to be associated with unfavorable outcome,[213,265,269-271] with EFS at 2 years less than 20% in two reports that included 28 patients.[213,269,271]
  • KMT2A-rearranged: Cases with KMT2A translocations represent 10% to 17% of pediatric AMKL, with MLLT3 (AF9) being the most common KMT2A fusion partner.[213,249,270] KMT2A-rearranged cases appear to be associated with inferior outcome among children with AMKL, with OS rates at 4 to 5 years of approximately 30%.[213,249,270] An international collaboration evaluating pediatric AMKL observed that the presence of t(9;11)/MLLT3-KMT2A, which was seen in approximately 5% of AMKL cases (n = 21), was associated with an inferior outcome (5-year OS, approximately 20%) compared with other AMKL cases and other KMT2A-rearrangements (n = 17), each with a 5-year OS of 50% to 55%.[249] Inferior outcome was not observed for patients (n = 17) with other KMT2A-rearrangements.
  • NUP98-KDM5A4: NUP98-KDM5A4 is observed in approximately 10% of pediatric AMKL cases [213,270] and is observed at much lower rates in non-AMKL cases.[271] NUP98-KDM5A4 cases showed a trend towards inferior prognosis, although the small number of cases studied limits confidence in this assessment.[213,270]
  • RBM15-MKL1: The t(1;22)(p13;q13) translocation that produces RBM15-MKL1 is uncommon (<1% of pediatric AML) and is restricted to acute megakaryocytic leukemia (AMKL).[163,271-276] Studies have found that t(1;22)(p13;q13) is observed in 10% to 18% of children with AMKL who have evaluable cytogenetics or molecular genetics.[213,249,270] Most AMKL cases with t(1;22) occur in infants, with the median age at presentation (4–7 months) being younger than that for other children with AMKL.[249,267,277] Cases with detectable RBM15-MKL1 fusion transcripts in the absence of t(1;22) have also been reported because these young patients usually have hypoplastic bone marrow.[274]
    An international collaborative retrospective study of 51 t(1;22) cases reported that patients with this abnormality had a 5-year EFS of 54.5% and an OS of 58.2%, similar to the rates for other children with AMKL.[249] In another international retrospective analysis of 153 cases with non–Down syndrome AMKL who had samples available for molecular analysis, the 4-year EFS for patients with t(1;22) was 59% and OS was 70%, significantly better than AMKL patients with other specific genetic abnormalities (CBFA2T3/GUS2, NUP98/KDM5A4, KMT2Arearrangements, monosomy 7).[270]
  • HOX-rearranged: Cases with a gene fusion involving a HOX cluster gene represented 15% of pediatric AMKL in one report.[213] This report observed that these patients appear to have a relatively favorable prognosis, although the small number of cases studied limits confidence in this assessment.
  • GATA1 mutated: GATA1-truncating mutations in non–Down syndrome AMKL arise in young children (median age, 1–2 years) and are associated with amplification of the Down syndrome critical region on chromosome 21.[213] These patients represented approximately 10% of non–Down syndrome AMKL and appeared to have a favorable outcome if there were no prognostically unfavorable fusion genes also present, although the number of patients studied was small (n = 8).[213]
• t(8;16) (MYST3-CREBBP): The t(8;16) translocation fuses the MYST3 gene on chromosome 8p11 to CREBBP on chromosome 16p13. t(8;16) AML rarely occurs in children. In an international Berlin-Frankfurt-Münster (BFM) AML study of 62 children, presence of this translocation was associated with younger age at diagnosis (median, 1.2 years), FAB M4/M5 phenotype, erythrophagocytosis, leukemia cutis, and disseminated intravascular coagulation.[278] Outcome for children with t(8;16) AML appears similar to other types of AML.
  A substantial proportion of infants diagnosed with t(8;16) AML in the first month of life show spontaneous remission, although AML recurrence may occur months to years later.[278-284] These observations suggest that a watch and wait policy could be considered in cases of t(8;16) AML diagnosed in the neonatal period if close long-term monitoring can be ensured.[278]
• t(7;12)(q36;p13): The t(7;12)(q36;p13) translocation involves ETV6 on chromosome 12p13 and variable breakpoints on chromosome 7q36 in the region of MNX1 (HLXB9).[285] The translocation may be cryptic by conventional karyotyping and in some cases may be confirmed only by FISH.[286-288] This alteration occurs virtually exclusively in children younger than 2 years, is mutually exclusive with the KMT2A (MLL) rearrangement, and is associated with a high risk of treatment failure.[163,164,200,286,287,289]
• NUP98 gene fusions: NUP98 has been reported to form leukemogenic gene fusions with more than 20 different partners.[290] In the pediatric AML setting, the two most common fusion genes are NUP98-NSD1 and NUP98-KDM5A4 (JARID1A), with the former observed in one report in approximately 15% of cytogenetically normal pediatric AML and the latter observed in approximately 10% of pediatric AMKL (see above).[213,235,267] AML cases with either NUP98 fusion gene show high expression of HOXAand HOXB genes, indicative of a stem cell phenotype.[260,267]
  The NUP98-NSD1 fusion gene, which is often cytogenetically cryptic, results from the fusion of NUP98 (chromosome 11p15) with NSD1 (chromosome 5q35).[235,236,260,291-294] This alteration occurs in approximately 4% to 7% of pediatric AML cases.[20,170,235,260,293] The highest frequency in the pediatric population is in the 5- to 9-year age group (approximately 8%), with lower frequency in younger children (approximately 2% in children younger than 2 years). NUP98-NSD1 cases present with high WBC count (median, 147 × 109/L in one study).[235,236] Most NUP98-NSD1 AML cases do not show cytogenetic aberrations.[235,260,291] A high percentage of NUP98-NSD1 cases (74% to 90%) have FLT3-ITD.[170,235,236]
  A study that included 12 children with NUP98-NSD1 AML reported that although all patients achieved CR, presence of NUP98-NSD1 independently predicted poor prognosis, and children with NUP98-NSD1 AML had a high risk of relapse, with a resulting 4-year EFS of approximately 10%.[235] In another study that included children (n = 38) and adults (n = 7) with NUP98-NSD1 AML, presence of both NUP98-NSD1 and FLT3-ITD independently predicted poor prognosis; patients with both lesions had a low CR rate (approximately 30%) and a low 3-year EFS rate (approximately 15%).[236]
• RUNX1 mutations: AML with mutated RUNX1, which is a provisional entity in the 2016 WHO classification of AML and related neoplasms, is more common in adults than in children. In adults, the RUNX1 mutation is associated with a high risk of treatment failure. In a study of children with AML, RUNX1 mutations were observed in 11 of 503 patients (approximately 2%). Six of 11 patients with RUNX1-mutated AML failed to achieve remission and their 5-year EFS was 9%, suggesting that the RUNX1 mutation confers a poor prognosis in both children and adults.[295]
• RAS mutations: Although mutations in RAS have been identified in 20% to 25% of patients with AML, the prognostic significance of these mutations has not been clearly shown.[200,296-298] Mutations in NRAS are observed more commonly than mutations in KRAS in pediatric AML cases.[200,299] RAS mutations occur with similar frequency for all Type II alteration subtypes, with the exception of APL, for which RAS mutations are seldom observed.[200]
• KIT mutations: Mutations in KIT occur in approximately 5% of AML, but in 10% to 40% of AML with core-binding factor abnormalities.[200,299-301]
  The presence of activating KIT mutations in adults with this AML subtype appears to be associated with a poorer prognosis compared with core-binding factor AML without KITmutations.[300,302,303] The prognostic significance of KIT mutations occurring in pediatric core-binding factor AML remains unclear,[304-307] although the largest pediatric study reported to date observed no prognostic significance for KIT mutations.[308]
• WT1 mutations: WT1, a zinc-finger protein regulating gene transcription, is mutated in approximately 10% of cytogenetically normal cases of AML in adults.[309-312] The WT1mutation has been shown in some,[309,310,312] but not all studies [311] to be an independent predictor of worse disease-free survival, EFS, and OS of adults.
  In children with AML, WT1 mutations are observed in approximately 10% of cases.[313,314] Cases with WT1 mutations are enriched among children with normal cytogenetics and FLT3-ITD, but are less common among children younger than 3 years.[313,314] AML cases with NUP98-NSD1 are enriched for both FLT3-ITD and WT1mutations.[235] In univariate analyses, WT1 mutations are predictive of poorer outcome in pediatric patients, but the independent prognostic significance of WT1mutation status is unclear because of its strong association with FLT3-ITD and its association with NUP98-NSD1.[235,313,314] The largest study of WT1 mutations in children with AML observed that children with WT1 mutations in the absence of FLT3-ITD had outcomes similar to that of children without WT1 mutations, while children with both WT1 mutation and FLT3-ITD had survival rates less than 20%.[313]
• DNMT3A mutations: Mutations of the DNMT3A gene have been identified in approximately 20% of adult AML patients and are uncommon in patients with favorable cytogenetics but occur in one-third of adult patients with intermediate-risk cytogenetics.[315] Mutations in this gene are independently associated with poor outcome.[315-317] DNMT3A mutations are virtually absent in children.[318]
• IDH1 and IDH2 mutations: Mutations in IDH1 and IDH2, which code for isocitrate dehydrogenase, occur in approximately 20% of adults with AML,[319-323] and they are enriched in patients with NPM1 mutations.[320,321,324] The specific mutations that occur in IDH1 and IDH2 create a novel enzymatic activity that promotes conversion of alpha-ketoglutarate to 2-hydroxyglutarate.[325,326] This novel activity appears to induce a DNA hypermethylation phenotype similar to that observed in AML cases with loss of function mutations in TET2.[324]
  Mutations in IDH1 and IDH2 are rare in pediatric AML, occurring in 0% to 4% of cases.[318,327-331] There is no indication of a negative prognostic effect for IDH1 and IDH2mutations in children with AML.[327]
• CSF3R mutations: CSF3R is the gene encoding the granulocyte colony-stimulating factor (G-CSF) receptor, and activating mutations in CSF3R are observed in 2% to 3% of pediatric AML cases.[332] These mutations lead to enhanced signaling through the G-CSF receptor, and they are primarily observed in AML with either CEBPA mutations or with core-binding factor abnormalities (RUNX1-RUNX1T1 and CBFB-MYH11).[332] The clinical characteristics of and prognosis for patients with CSF3R mutations do not seem to be significantly different from those of patients without CSF3R mutations.
  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.[333] In one study of patients with severe congenital neutropenia, 34% of patients who had not developed a myeloid malignancy had CSF3R mutations detectable in peripheral blood neutrophils and mononuclear cells, while 78% of patients who had developed a myeloid malignancy showed CSF3R mutations.[333] A study of 31 patients with severe congenital neutropenia who developed AML or MDS observed CSF3Rmutations in approximately 80%, and also observed a high frequency of RUNX1mutations (approximately 60%), suggesting cooperation between CSF3R and RUNX1mutations for leukemia development within the context of severe congenital neutropenia.[334]

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

Juvenile Myelomonocytic Leukemia (JMML)

The genomic landscape of JMML is characterized by mutations in one of five genes of the Ras pathway: NF1, NRAS, KRAS, PTPN11, and CBL.[335-337] In a series of 118 consecutively diagnosed JMML cases with Ras pathway–activating mutations, PTPN11 was the most commonly mutated gene, accounting for 51% of cases (19% germline and 32% somatic) (refer to Figure 3).[335] 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,[335-337] a finding that is associated with poorer prognosis.[335,337]

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.[335-337] 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., SETBP1was mutated in 6%–9% of cases).[335-338] JAK3 mutations are also observed in a small percentage (4%–12%) of JMML cases.[335-338] Cases with germline PTPN11 and germline CBL mutations showed low rates of additional mutations (refer to Figure 3).[335] The presence of mutations beyond disease-defining Ras pathway mutations is associated with an inferior prognosis.[335,336]

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.[337]

ENLARGE

Figure 3. 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 GeneticsExit Disclaimer (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).

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

• Number of non-RAS pathway mutations. A strong predictor of prognosis for children with JMML is the number of mutations beyond the disease-defining RAS-pathway mutations.[335,336] Of 64 patients (65.3%) at diagnosis, zero or one somatic alteration (pathogenic mutation or monosomy 7) was identified, whereas two or more alterations were identified in 34 (34.7%) patients.[336] In multivariate analysis, mutation number (two or more vs. zero or one) maintained significance as a predictor of inferior event-free survival and overall survival. A higher proportion of patients diagnosed with two or more alterations were older and male, and these patients also demonstrated a higher rate of monosomy 7 or somatic NF1 mutation.[336] Similar findings and observations reported that patients with RAS-pathway double mutations (15 of 96 patients) were at the highest risk of treatment failure.[335]
• RAS-MAPK pathway inhibitors. Because JMML is a disease defined by mutations in the RAS-MAPK pathway, one might speculate that inhibitors of this pathway (e.g., MEK inhibitors) may have clinical utility in the treatment of JMML. However, preclinical data to support this hypothesis are inconsistent,[339,340] and there are no clinical data available.

Myelodysplastic Syndromes (MDS)

Pediatric myelodysplastic syndromes (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.[341,342]

A report of the genomic landscape of pediatric MDS described the results of whole-exome sequencing for 32 pediatric primary MDS patients and targeted sequencing for another 14 cases.[341] These 46 cases were equally divided between refractory cytopenia of childhood and MDS with excess blasts (MDS-EB). The results from the report include the following:

• Mutations in Ras/MAPK pathway genes were observed in 43% of primary MDS cases, with mutations most commonly involving PTPN11 and NRAS but with mutations also observed in other pathway members (e.g., BRAF [non–BRAF V600E], CBL, and KRAS). Ras/MAPK mutations were more common in patients with MDS-EB (65%) than in patients with refractory cytopenia of childhood (17%).
• Germline variants in SAMD9 (n = 4) or SAMD9L (n = 4) were observed in 17% of patients with primary MDS, with seven of eight mutations occurring in patients with refractory cytopenia of childhood. These cases all showed loss of material on chromosome 7. Approximately 40% of patients with deletions of part or all of chromosome 7 had germline SAMD9 or SAMD9L variants.
• GATA2 mutations were observed in three cases (7%), and all cases were confirmed or presumed to be germline.
• Deletions involving chromosome 7 were the most common copy number alteration and were observed in 41% of cases. Loss of part or all of chromosome 7 was most commonly observed in SAMD9/SAMD9L cases (100%) and in MDS-EB patients with a Ras/MAPK mutation (71%).
• Other genes that were mutated in more than 1 of the 46 cases studied included SETBP1, ETV6, and TP53.

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%).[341,342] SAMD9 and SAMD9L were not included in the gene panel. The second report described the following results:

• Germline GATA2 mutations were observed in 30% of patients, and RUNX1 mutations were observed in 6% of patients.
• Somatic mutations were observed in 34% of patients and were more common in patients with MDS-EB than in patients with refractory cytopenia of childhood (68% vs. 13%).
• The most commonly mutated gene was SETBP1 (18%); less commonly mutated genes included ASXL1, RUNX1, and Ras/MAPK pathway genes (PTPN11, NRAS, KRAS, NF1). Twelve percent of cases showed mutations in Ras/MAPK pathway genes.

Patients with germline GATA2 mutations, in addition to MDS, show a wide range of hematopoietic and immune defects as well as nonhematopoietic manifestations.[343] The former defects include monocytopenia with susceptibility to atypical mycobacterial infection and DCML deficiency (loss of dendritic cells, monocytes, and B and natural killer lymphoid cells). The resulting immunodeficiency leads to increased susceptibility to warts, severe viral infections, mycobacterial infections, fungal infections, and human papillomavirus–related cancers. The nonhematopoietic manifestations include deafness and lymphedema. Germline GATA2 mutations were studied in 426 pediatric patients with primary MDS and 82 cases with secondary MDS who were enrolled in consecutive studies of the European Working Group of MDS in Childhood (EWOG-MDS).[344] The study had the following results:

• Germline GATA2 mutations were identified in 7% of pediatric patients with primary MDS. While the median age of patients presenting with GATA2 mutations was 12.3 years in the EWOG-MDS pediatric population, most cases of germline GATA2-related myeloid neoplasms occur during adulthood.[345]
• GATA2 mutations were more common in patients with MDS-EB (15%) than in patients with refractory cytopenia of childhood (4%).
• Among patients with GATA2 mutations, 46% presented with MDS-EB and 70% showed monosomy 7.
• Familial MDS/AML was identified in 12 of 53 GATA2-mutated patients for whom detailed family histories were available.
• Nonhematologic phenotypes of GATA2 deficiency were present in 51% of GATA2-mutated patients with MDS and included deafness (9%), lymphedema/hydrocele (23%), and immunodeficiency (39%).

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.[346] In 2016, SAMD9 was identified as the cause of the MIRAGE syndrome (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy), which is associated with early-onset MDS with monosomy 7.[347] Subsequently, mutations in SAMD9L were identified in patients with ataxia pancytopenia syndrome (ATXPC; OMIM 159550Exit Disclaimer). SAMD9and SAMD9L mutations were also identified as the cause of myelodysplasia and leukemia syndrome with monosomy 7 (MLSM7; OMIM 252270Exit Disclaimer),[348] a syndrome first identified in phenotypically normal siblings who developed MDS or AML associated with monosomy 7 during childhood.[349]

• Causative mutations in both SAMD9 and SAMD9L are gain-of-function mutations and enhance the growth-suppressing activity of SAMD9/SAMD9L.[347,349]
• Both SAMD9 and SAMD9L are located at chromosome 7q21.2. Cases of MDS in patients with SAMD9 or SAMD9L mutations often show monosomy 7, with the remaining chromosome 7 having wild-type SAMD9/SAMD9L. This results in the loss of the enhanced growth-suppressing activity of the mutated gene.
• Phenotypically normal patients with SAMD9/SAMD9L mutations and monosomy 7 may progress to MDS or AML or, alternatively, may show loss of their monosomy 7 with a return of normal hematopoiesis.[349] The former outcome is associated with the acquisition of mutations in genes associated with MDS/AML (e.g., ETV6 or SETBP1), while the latter is associated with genetic alterations (e.g., revertant mutations or copy-neutral loss of heterozygosity with retention of the wild-type allele) that result in normalization of SAMD9/SAMD9L activity. These observations suggest that monitoring of patients with SAMD9/SAMD9L-related monosomy 7 using clinical sequencing for acquired mutations in genes associated with progression to AML may identify patients at high risk of leukemic transformation who may benefit most from hematopoietic stem cell transplantation.[349]

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248. Pui CH, Relling MV, Rivera GK, et al.: Epipodophyllotoxin-related acute myeloid leukemia: a study of 35 cases. Leukemia 9 (12): 1990-6, 1995. [PUBMED Abstract]
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265. Gruber TA, Larson Gedman A, Zhang J, et al.: An Inv(16)(p13.3q24.3)-encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia. Cancer Cell 22 (5): 683-97, 2012. [PUBMED Abstract]
266. Thiollier C, Lopez CK, Gerby B, et al.: Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models. J Exp Med 209 (11): 2017-31, 2012. [PUBMED Abstract]
267. de Rooij JD, Hollink IH, Arentsen-Peters ST, et al.: NUP98/JARID1A is a novel recurrent abnormality in pediatric acute megakaryoblastic leukemia with a distinct HOX gene expression pattern. Leukemia 27 (12): 2280-8, 2013. [PUBMED Abstract]
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274. Duchayne E, Fenneteau O, Pages MP, et al.: Acute megakaryoblastic leukaemia: a national clinical and biological study of 53 adult and childhood cases by the Groupe Français d'Hématologie Cellulaire (GFHC). Leuk Lymphoma 44 (1): 49-58, 2003. [PUBMED Abstract]
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278. Coenen EA, Zwaan CM, Reinhardt D, et al.: Pediatric acute myeloid leukemia with t(8;16)(p11;p13), a distinct clinical and biological entity: a collaborative study by the International-Berlin-Frankfurt-Munster AML-study group. Blood 122 (15): 2704-13, 2013. [PUBMED Abstract]
279. Wong KF, Yuen HL, Siu LL, et al.: t(8;16)(p11;p13) predisposes to a transient but potentially recurring neonatal leukemia. Hum Pathol 39 (11): 1702-7, 2008. [PUBMED Abstract]
280. Wu X, Sulavik D, Roulston D, et al.: Spontaneous remission of congenital acute myeloid leukemia with t(8;16)(p11;13). Pediatr Blood Cancer 56 (2): 331-2, 2011. [PUBMED Abstract]
281. Terui K, Sato T, Sasaki S, et al.: Two novel variants of MOZ-CBP fusion transcripts in spontaneously remitted infant leukemia with t(1;16;8)(p13;p13;p11), a new variant of t(8;16)(p11;p13). Haematologica 93 (10): 1591-3, 2008. [PUBMED Abstract]
282. Sainati L, Bolcato S, Cocito MG, et al.: Transient acute monoblastic leukemia with reciprocal (8;16)(p11;p13) translocation. Pediatr Hematol Oncol 13 (2): 151-7, 1996 Mar-Apr. [PUBMED Abstract]
283. Weintraub M, Kaplinsky C, Amariglio N, et al.: Spontaneous regression of congenital leukaemia with an 8;16 translocation. Br J Haematol 111 (2): 641-3, 2000. [PUBMED Abstract]
284. Classen CF, Behnisch W, Reinhardt D, et al.: Spontaneous complete and sustained remission of a rearrangement CBP (16p13)-positive disseminated congenital myelosarcoma. Ann Hematol 84 (4): 274-5, 2005. [PUBMED Abstract]
285. Beverloo HB, Panagopoulos I, Isaksson M, et al.: Fusion of the homeobox gene HLXB9 and the ETV6 gene in infant acute myeloid leukemias with the t(7;12)(q36;p13). Cancer Res 61 (14): 5374-7, 2001. [PUBMED Abstract]
286. Slater RM, von Drunen E, Kroes WG, et al.: t(7;12)(q36;p13) and t(7;12)(q32;p13)--translocations involving ETV6 in children 18 months of age or younger with myeloid disorders. Leukemia 15 (6): 915-20, 2001. [PUBMED Abstract]
287. von Bergh AR, van Drunen E, van Wering ER, et al.: High incidence of t(7;12)(q36;p13) in infant AML but not in infant ALL, with a dismal outcome and ectopic expression of HLXB9. Genes Chromosomes Cancer 45 (8): 731-9, 2006. [PUBMED Abstract]
288. Tosi S, Harbott J, Teigler-Schlegel A, et al.: t(7;12)(q36;p13), a new recurrent translocation involving ETV6 in infant leukemia. Genes Chromosomes Cancer 29 (4): 325-32, 2000. [PUBMED Abstract]
289. Park J, Kim M, Lim J, et al.: Three-way complex translocations in infant acute myeloid leukemia with t(7;12)(q36;p13): the incidence and correlation of a HLXB9 overexpression. Cancer Genet Cytogenet 191 (2): 102-5, 2009. [PUBMED Abstract]
290. Takeda A, Yaseen NR: Nucleoporins and nucleocytoplasmic transport in hematologic malignancies. Semin Cancer Biol 27: 3-10, 2014. [PUBMED Abstract]
291. Brown J, Jawad M, Twigg SR, et al.: A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. Blood 99 (7): 2526-31, 2002. [PUBMED Abstract]
292. Panarello C, Rosanda C, Morerio C: Cryptic translocation t(5;11)(q35;p15.5) with involvement of the NSD1 and NUP98 genes without 5q deletion in childhood acute myeloid leukemia. Genes Chromosomes Cancer 35 (3): 277-81, 2002. [PUBMED Abstract]
293. Cerveira N, Correia C, Dória S, et al.: Frequency of NUP98-NSD1 fusion transcript in childhood acute myeloid leukaemia. Leukemia 17 (11): 2244-7, 2003. [PUBMED Abstract]
294. Jaju RJ, Fidler C, Haas OA, et al.: A novel gene, NSD1, is fused to NUP98 in the t(5;11)(q35;p15.5) in de novo childhood acute myeloid leukemia. Blood 98 (4): 1264-7, 2001. [PUBMED Abstract]
295. Yamato G, Shiba N, Yoshida K, et al.: RUNX1 mutations in pediatric acute myeloid leukemia are associated with distinct genetic features and an inferior prognosis. Blood 131 (20): 2266-2270, 2018. [PUBMED Abstract]
296. Radich JP, Kopecky KJ, Willman CL, et al.: N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 76 (4): 801-7, 1990. [PUBMED Abstract]
297. Farr C, Gill R, Katz F, et al.: Analysis of ras gene mutations in childhood myeloid leukaemia. Br J Haematol 77 (3): 323-7, 1991. [PUBMED Abstract]
298. Berman JN, Gerbing RB, Alonzo TA, et al.: Prevalence and clinical implications of NRAS mutations in childhood AML: a report from the Children's Oncology Group. Leukemia 25 (6): 1039-42, 2011. [PUBMED Abstract]
299. Kühn MW, Radtke I, Bullinger L, et al.: High-resolution genomic profiling of adult and pediatric core-binding factor acute myeloid leukemia reveals new recurrent genomic alterations. Blood 119 (10): e67-75, 2012. [PUBMED Abstract]
300. Schnittger S, Kohl TM, Haferlach T, et al.: KIT-D816 mutations in AML1-ETO-positive AML are associated with impaired event-free and overall survival. Blood 107 (5): 1791-9, 2006. [PUBMED Abstract]
301. Tokumasu M, Murata C, Shimada A, et al.: Adverse prognostic impact of KIT mutations in childhood CBF-AML: the results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial. Leukemia 29 (12): 2438-41, 2015. [PUBMED Abstract]
302. Cairoli R, Beghini A, Grillo G, et al.: Prognostic impact of c-KIT mutations in core binding factor leukemias: an Italian retrospective study. Blood 107 (9): 3463-8, 2006. [PUBMED Abstract]
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306. Goemans BF, Zwaan CM, Miller M, et al.: Mutations in KIT and RAS are frequent events in pediatric core-binding factor acute myeloid leukemia. Leukemia 19 (9): 1536-42, 2005. [PUBMED Abstract]
307. Boissel N, Leroy H, Brethon B, et al.: Incidence and prognostic impact of c-Kit, FLT3, and Ras gene mutations in core binding factor acute myeloid leukemia (CBF-AML). Leukemia 20 (6): 965-70, 2006. [PUBMED Abstract]
308. Pollard JA, Alonzo TA, Gerbing RB, et al.: Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML. Blood 115 (12): 2372-9, 2010. [PUBMED Abstract]
309. Paschka P, Marcucci G, Ruppert AS, et al.: Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study. J Clin Oncol 26 (28): 4595-602, 2008. [PUBMED Abstract]
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311. Gaidzik VI, Schlenk RF, Moschny S, et al.: Prognostic impact of WT1 mutations in cytogenetically normal acute myeloid leukemia: a study of the German-Austrian AML Study Group. Blood 113 (19): 4505-11, 2009. [PUBMED Abstract]
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313. Ho PA, Zeng R, Alonzo TA, et al.: Prevalence and prognostic implications of WT1 mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group. Blood 116 (5): 702-10, 2010. [PUBMED Abstract]
314. Hollink IH, van den Heuvel-Eibrink MM, Zimmermann M, et al.: Clinical relevance of Wilms tumor 1 gene mutations in childhood acute myeloid leukemia. Blood 113 (23): 5951-60, 2009. [PUBMED Abstract]
315. Ley TJ, Ding L, Walter MJ, et al.: DNMT3A mutations in acute myeloid leukemia. N Engl J Med 363 (25): 2424-33, 2010. [PUBMED Abstract]
316. Yan XJ, Xu J, Gu ZH, et al.: Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet 43 (4): 309-15, 2011. [PUBMED Abstract]
317. Thol F, Damm F, Lüdeking A, et al.: Incidence and prognostic influence of DNMT3A mutations in acute myeloid leukemia. J Clin Oncol 29 (21): 2889-96, 2011. [PUBMED Abstract]
318. Ho PA, Kutny MA, Alonzo TA, et al.: Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group. Pediatr Blood Cancer 57 (2): 204-9, 2011. [PUBMED Abstract]
319. Green CL, Evans CM, Hills RK, et al.: The prognostic significance of IDH1 mutations in younger adult patients with acute myeloid leukemia is dependent on FLT3/ITD status. Blood 116 (15): 2779-82, 2010. [PUBMED Abstract]
320. Paschka P, Schlenk RF, Gaidzik VI, et al.: IDH1 and IDH2 mutations are frequent genetic alterations in acute myeloid leukemia and confer adverse prognosis in cytogenetically normal acute myeloid leukemia with NPM1 mutation without FLT3 internal tandem duplication. J Clin Oncol 28 (22): 3636-43, 2010. [PUBMED Abstract]
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329. Pigazzi M, Ferrari G, Masetti R, et al.: Low prevalence of IDH1 gene mutation in childhood AML in Italy. Leukemia 25 (1): 173-4, 2011. [PUBMED Abstract]
330. Ho PA, Alonzo TA, Kopecky KJ, et al.: Molecular alterations of the IDH1 gene in AML: a Children's Oncology Group and Southwest Oncology Group study. Leukemia 24 (5): 909-13, 2010. [PUBMED Abstract]
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332. Maxson JE, Ries RE, Wang YC, et al.: CSF3R mutations have a high degree of overlap with CEBPA mutations in pediatric AML. Blood 127 (24): 3094-8, 2016. [PUBMED Abstract]
333. Germeshausen M, Kratz CP, Ballmaier M, et al.: RAS and CSF3R mutations in severe congenital neutropenia. Blood 114 (16): 3504-5, 2009. [PUBMED Abstract]
334. Skokowa J, Steinemann D, Katsman-Kuipers JE, et al.: Cooperativity of RUNX1 and CSF3R mutations in severe congenital neutropenia: a unique pathway in myeloid leukemogenesis. Blood 123 (14): 2229-37, 2014. [PUBMED Abstract]
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336. Stieglitz E, Taylor-Weiner AN, Chang TY, et al.: The genomic landscape of juvenile myelomonocytic leukemia. Nat Genet 47 (11): 1326-33, 2015. [PUBMED Abstract]
337. Murakami N, Okuno Y, Yoshida K, et al.: Integrated molecular profiling of juvenile myelomonocytic leukemia. Blood 131 (14): 1576-1586, 2018. [PUBMED Abstract]
338. Sakaguchi H, Okuno Y, Muramatsu H, et al.: Exome sequencing identifies secondary mutations of SETBP1 and JAK3 in juvenile myelomonocytic leukemia. Nat Genet 45 (8): 937-41, 2013. [PUBMED Abstract]
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340. Chang T, Krisman K, Theobald EH, et al.: Sustained MEK inhibition abrogates myeloproliferative disease in Nf1 mutant mice. J Clin Invest 123 (1): 335-9, 2013. [PUBMED Abstract]
341. Schwartz JR, Ma J, Lamprecht T, et al.: The genomic landscape of pediatric myelodysplastic syndromes. Nat Commun 8 (1): 1557, 2017. [PUBMED Abstract]
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