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Ref Type Journal Article
PMID (26522332)
Authors Moriyama T, Metzger ML, Wu G, Nishii R, Qian M, Devidas M, Yang W, Cheng C, Cao X, Quinn E, Raimondi S, Gastier-Foster JM, Raetz E, Larsen E, Martin PL, Bowman WP, Winick N, Komada Y, Wang S, Edmonson M, Xu H, Mardis E, Fulton R, Pui CH, Mullighan C, Evans WE, Zhang J, Hunger SP, Relling MV, Nichols KE, Loh ML, Yang JJ
Title Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study.
Journal The Lancet. Oncology
Vol 16
Issue 16
Date 2015 Dec
URL
Abstract Text Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL.Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment 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 characterised bioinformatically and correlated with clinical and demographic features in children with ALL.We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050).Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed.US National Institutes of Health and American Lebanese Syrian Associated Charities.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ETV6 R199Q missense unknown ETV6 R199Q lies within the linker domain of the Etv6 protein (PMID: 25581430). R199Q has been identified in sequencing studies (PMID: 26522332), but has not been biochemically characterized and therefore, its effect on Etv6 protein function is unknown (PubMed, Apr 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ETV6 inact mut acute lymphoblastic leukemia not applicable N/A Clinical Study Risk Factor In multiple clinical studies, ETV6 inactivating germline mutations were shown to be a risk factor for the development of acute lymphocytic leukemia (PMID: 26522332, PMID: 26102509, PMID: 25807284). 25807284 26102509 26522332