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

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Weigelt, Britta 
Bi, Rui 
Kumar, Rahul 
Blecua, Pedro 
Mandelker, Diana L 

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.

alleles, phenotype, mutation, ataxia-telangiectasia, hormone receptors, brcal protein, dna, dna damage, genes, brcal gene, tp53 gene, germ-line mutation, loss of heterozygosity, protein p53, recombination, genetic, genetics, neoplasms, breast cancer, somatic mutation, biopharmaceutics classification system, infiltrates, cell cycle checkpoint, exome, datasets
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Journal of the National Cancer Institute
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Cancer Research Uk (None)
Cancer Research Uk (None)
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