The Landscape of Somatic Genetic Alterations in Breast Cancers From ATM Germline Mutation Carriers

• Published in: JNCI : Journal of the National Cancer Institute Vol. 110; no. 9; pp. 1030 - 1034
• Main Authors: Weigelt, Britta, Bi, Rui, Kumar, Rahul, Blecua, Pedro, Mandelker, Diana L, Geyer, Felipe C, Pareja, Fresia, James, Paul A, Couch, Fergus J, Eccles, Diana M, Blows, Fiona, Pharoah, Paul, Li, Anqi, Selenica, Pier, Lim, Raymond S, Jayakumaran, Gowtham, Waddell, Nic, Shen, Ronglai, Norton, Larry, Wen, Hannah Y, Powell, Simon N, Riaz, Nadeem, Robson, Mark E, Reis-Filho, Jorge S, Chenevix-Trench, Georgia
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.09.2018
• Subjects: Adult; Aged; Ataxia Telangiectasia Mutated Proteins - genetics; Biomarkers, Tumor; Breast Neoplasms - diagnosis; Breast Neoplasms - genetics; Brief Communications; Exome Sequencing; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genomics - methods; Germ-Line Mutation; Heterozygote; Humans; Middle Aged; Mutation
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djy028

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. ATM-associated 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.