Abstract 2033: Germline mutations in ETV6 confer risk of thrombocytopenia and acute lymphocytic leukemia
Authors: Joseph Vijai , Walsh Michael F. , Topka Sabine , Wu Gang , McGee Rose B. , Quinn Emily , Inaba Hiroto , Hartford Christine , Pui Ching-Hon , Pappo Alberto S. , Edmonson Michael , Jacobs Lauren , Danylo Villano , Schrader Kasmintan , Gaddam Pragna , Stadler Zsofia , Zhang Michael , Stepensky Polina , Steinherz Peter , Bussel James , Harit M , Weintraub Michael , Shimamura Akiko , Zhang Jinghui , Downing James R. , Offit Kenneth , Nichols Kim E. 
Published: August 2015

Abstract
Germline mutations of transcription factors (e.g. PAX5, CEBPA, GATA2, RUNX1) have been associated with an inherited susceptibility to acute leukemia. Here we report 2 unrelated kindreds harboring germline mutations in ETV6, the gene encoding the transcription factor ETS variants 6. These kindreds were primarily characterized by thrombocytopenia and acute lymphoblastic leukemia (ALL). The first kindred, identified at MSKCC and HMC, includes 9 individuals with thrombocytopenia, and 3 individuals with pre-B ALL. Sequencing a subset of common and somatically altered leukemia genes in this family identified a rare heterozygous non-synonymous missense variation (T&gt;C) in 6 family members with thrombocytopenia and 2 with ALL. Notably, this variant did not segregate in 9 individuals in the kindred without these phenotypes. The amino acid alteration is predicted to lead to an L349P substitution within the DNA binding domain of ETV6 (L349P, NPP_001978). In silico analyses using SIFT and Polyphen assigned pathogenic variant classifications to the L349P variant. The proband of the second family presented to SJCRH with pre-B ALL, a history of thrombocytopenia, and demonstrated hypersensitivity to methotrexate (grade 3 bone marrow suppression). His leukemia transformated to myelodsyplastic syndrome and acute myeloid leukemia, which was treated by unrelated donor transplantation. The proband's mother, maternal aunt and maternal grandfather had thrombocytopenia, and the maternal great grandfather was diagnosed with chronic myeloid leukemia. The proband and his mother were found to carry a heterozygous 5 bp deletion in ETV6, N385fs (c.1153-5_1153_1delAACAG), which is predicted to produce a truncated protein of 389 amino acids with the last 4 residues different from the canonical ETV6 sequence. This variant has not been described in public sequencing data repositories. Finally, a review of 1,120 cases from the SJCRH/Washington University Pediatric Cancer Genome Project, including 588 cases of leukemia (among which 472 were ALL), revealed 3 rare germline ETV6 variants: L442P (n = 1), R181H (n = 1), and V37M (n = 1), with 2 of these variants L442P and R181H predicted to be pathogenic based on prediction and/or genomic location. Notably, these 2 variants each occurred in patients with ALL.
Collectively, these findings suggest that germline ETV6 mutations are associated with a novel syndrome of thrombocytopenia with susceptibility to leukemia. Furthermore, these mutations may account for approximately 0.4% (2/472) of pediatric ALL cases. Further phenotypic characterization of affected patients and functional assessment of ETV6 germline variants, in progress, will be required to reveal the clinical effects of these mutations, their incidence in patients with ALL and their role in leukemogenesis.
Citation Format: Vijai Joseph, Michael F. Walsh, Sabine Topka, Gang Wu, Rose B. McGee, Emily Quinn, Hiroto Inaba, Christine Hartford, Ching-Hon Pui, Alberto S. Pappo, Michael Edmonson, Lauren Jacobs, Villano Danylo, Kasmintan Schrader, Pragna Gaddam, Zsofia Stadler, Michael Zhang, Polina Stepensky, Peter Steinherz, James Bussel, M Harit, Michael Weintraub, Akiko Shimamura, Jinghui Zhang, James R. Downing, Kenneth Offit, Kim E. Nichols. Germline mutations in ETV6 confer risk of thrombocytopenia and acute lymphocytic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2033. doi:10.1158/1538-7445.AM2015-2033