@article{d1751e8db27d46fe977aec031c63ec69,
title = "The landscape of somatic genetic alterations in breast cancers from atm germline mutation carriers",
abstract = "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 fromATM germlinemutation carriers by whole-exome and targeted sequencing. ATMassociated BCs were consistently hormone receptor positive and largely displayedminimal immune infiltrate. Although 79.2% of these tumors exhibited loss of heterozygosity of the ATM wild-type allele, none displayed high activity ofmutational signature 3 associated with defective homologous recombination DNA (HRD) repair. No TP53mutations were found in the ATM-associated BCs. Analysis of an independent data set confirmed that germline ATMvariants and TP53 somaticmutations aremutually 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-relatedmutational signatures, and that TP53 and ATM genetic alterations are likely epistatic.",
author = "Britta Weigelt and Rui Bi and Rahul Kumar and Pedro Blecua and Mandelker, {Diana L.} and Geyer, {Felipe C.} and Fresia Pareja and James, {Paul A.} and Couch, {Fergus J.} and Eccles, {Diana M.} and Fiona Blows and Paul Pharoah and Anqi Li and Pier Selenica and Lim, {Raymond S.} and Gowtham Jayakumaran and Nic Waddell and Ronglai Shen and Larry Norton and Wen, {Hannah Y.} and Powell, {Simon N.} and Nadeem Riaz and Robson, {Mark E.} and Reis-Filho, {Jorge S.} and Georgia Chenevix-Trench",
note = "Funding Information: This work was supported in part by the Meredith Israel Thomas Fund, the Breast Cancer Research Foundation, the Sarah Jenkins Fund, a Cancer Center Support Grant from the National Institutes of Health (NIH)/National Cancer Institute (Grant No. P30CA008748), NIH grants CA192393 and CA176785, and a Sponsored Program of Research Excellence (SPORE) in Breast Cancer (P50 CA116201). GCT is supported by the National Health and Medical Research Council of Australia. Funding Information: We wish to thank Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, and the heads and staff of the Family Cancer Clinics and the Clinical Follow Up Study (which has received funding from the National Health and Medical Research Council [NHMRC], the National Breast Cancer Foundation, Cancer Australia, and the National Institute of Health) for their contributions to this resource, as well as the many families who contribute to kConFab. kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the NHMRC, the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania, and South Australia, and the Cancer Foundation of Western Australia. Linda Haywood provided technical support for sending cases from the POSH study, which was funded by Cancer Research UK (C1275/A11699).",
year = "2018",
month = sep,
day = "1",
doi = "10.1093/jnci/djy028",
language = "English (US)",
volume = "110",
pages = "1030--1034",
journal = "Journal of the National Cancer Institute",
issn = "0027-8874",
publisher = "Oxford University Press",
number = "9",
}