Abstract
BackgroundHereditary predisposition is rarely suspected for childhood acute lymphoblastic leukemia (ALL). Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL.MethodsWhole-exome sequencing of an index family with multiple cases of ALL was performed to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in 4,405 children from the Children's Oncology Group (COG) and St. Jude Children's Research Hospital frontline ALL trials. Patients were included in this study on the basis of their enrollment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterized bioinformatically and correlated with clinical and demographic features in 2,021 children with ALL.FindingsWe identified a novel nonsense ETV6 variant (p.R359X) with a high penetrance of familial ALL. Subsequent targeted sequencing of ETV6 in 4,405 childhood ALL cases discovered 31 exonic variants (4 nonsense, 21 missense, 1 splice site, and 5 frame shift variants) that are potentially related to ALL risk in 35 cases (0.79%). Fifteen (48%) of the 31 ALL-related ETV6 variants clustered in the ETS domain and predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukemia diagnosis than others (10.2 years [IQR 5.3-13.8] vs 4.7 years [IQR 3.0-8.7], P=0.017). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (9 of 14 cases [64.3%] vs 538 of 2,007 cases [26.8%]; P=0.0050).InterpretationOur findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL.FundingThis study was supported by the National Institutes of Health and by the American Lebanese Syrian Associated Charities.
Highlights
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and a prototype of cancer that can be cured by chemotherapy alone with risk-adapted chemotherapeutic regimens.[1,2,3,4] the etiology of this aggressive cancer remains largely unknown
A small fraction of acute lymphoblastic leukemia (ALL) cases are thought to be related to congenital genetic disorders (e.g., Down syndrome[18, 19], Robertsonian translocation20), and hereditary predisposition is rarely considered in clinical practice
Consistent with recent reports of recurring germline ETV6 mutations associated with familial thrombocytopenia and overrepresentation of hematologic malignancies,[29,30,31] this p.R359X variant in ETV6 is likely to be responsible for the ALL predisposition in this family
Summary
Acute lymphoblastic leukemia (ALL) is the most common cancer in children and a prototype of cancer that can be cured by chemotherapy alone with risk-adapted chemotherapeutic regimens.[1,2,3,4] the etiology of this aggressive cancer remains largely unknown. Recent studies of familial ALL have identified rare germline mutations in PAX5 and SH2B3 with high penetrance.[21, 22] More strikingly, germline TP53 mutations were found in ∼50% of children with low-hypodiploid ALL, suggesting that this subtype of ALL may be a manifestation of Li Fraumeni syndrome.[23] Together, these data raise the possibility that the proportion of ALL cases attributable to inherited genetic mutations may be much higher than currently proposed. Recent studies identified germline ETV6 variations associated with marked familial clustering of hematologic malignancies, pointing to this gene as a potentially important genetic determinant for ALL susceptibility. The aims of the current study are to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contribute to the overall risk of childhood ALL
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