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.
ASJC Scopus subject areas
- Cancer Research