OP-JNCI180033 1030..1034

Pathogenic germline variants in ataxia-telangiectasia mutated (ATM), a gene that plays a role in DNA damage response and cell cycle checkpoints, confer an increased breast cancer (BC) risk. Here, we investigated the phenotypic characteristics and landscape of somatic genetic alterations in 24 BCs from ATM germline mutation carriers by whole-exome and targeted sequencing. ATMassociated BCs were consistently hormone receptor positive and largely displayed minimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity of mutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53 mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATM variants and TP53 somatic mutations are mutually exclusive. Our findings indicate that ATM-associated BCs often harbor bi-allelic inactivation of ATM, are phenotypically distinct from BRCA1/2-associated BCs, lack HRD-related mutational signatures, and that TP53 and ATM genetic alterations are likely epistatic. The protein kinase ataxia-telangiectasia (ATM) plays a central role in the activation of DNA damage response following DNA double-strand breaks and in cell cycle checkpoint control (1). Heterozygous germline mutations in ATM occur in 1% of the population and are associated with increased breast cancer (BC) risk (2,3). In addition to germline nonsense and frameshift mutations, one rare ATM missense variant, c.7271T>G (p.V2424G), confers a particularly strong BC risk (2) and may act in a dominant-negative manner (4). Here, we assessed the phenotype and repertoire of somatic genetic alterations in BCs from 24 patients with germline pathogenic ATM variants, and whether somatic loss of heterozygosity (LOH) of the ATM wild-type allele occurs in these tumors. As a secondary aim, we set out to establish whether ATM-associated breast cancers harboring the c.7271T>G variant had genomic evidence supportive of its dominant-negative mode of action. Approval by the local ethics committees of the contributing authors’ institutions and patient written informed consents were obtained. The methods are detailed in the Supplementary Methods (available online). Two-sided P values of less than . 05 were considered statistically significant. For CoMEt, default settings and significance levels were adopted (5). Pathogenic germline variants in ATM comprised 15 (62.5%) missense mutations (all but one c.7271T>G), two (8.3%) nonsense mutations, five (20.8%) frameshift deletions, one (4.2%) in-frame deletion, and one (4.2%) large deletion (Supplementary Table 1, available online). The median age (range) of breast cancer diagnosis of the patients was 46 (32–79) years. All ATMassociated BCs included in this study were estrogen receptor (ER)-positive, four (16.7%) were human epidermal growth factor B R EF C O M M U N IC A T IO N Received: September 29, 2017; Revised: December 25, 2017; Accepted: February 6, 2018 © The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com 1030 JNCI J Natl Cancer Inst (2018) 110(9): djy028 doi: 10.1093/jnci/djy028 First published online February 28, 2018