Format

Send to

Choose Destination
J Natl Cancer Inst. 2018 Sep 1;110(9):1030-1034. doi: 10.1093/jnci/djy028.

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

Author information

1
Department of Pathology (BW, RB, RK, DLM, FCG, FP, AL, PS, RSL, GJ, HYW, JSRF) Memorial Sloan Kettering Cancer Center, New York, NY.
2
Department of Pathology, Fudan University Cancer Center, Shanghai, China (RB, AL).
3
Radiation Oncology (PB, SNP, NR) Memorial Sloan Kettering Cancer Center, New York, NY.
4
Familial Cancer Centre (PAJ) Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
5
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN (FJC).
6
Southampton Clinical Trials Unit, University of Southampton, Southampton, UK (DME).
7
Department of Oncology, University of Cambridge, Cambridge, UK (FB, PP).
8
QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia (NW, GCT).
9
Epidemiology and Biostatistics (RS) Memorial Sloan Kettering Cancer Center, New York, NY.
10
Department of Medicine (LN, MER) Memorial Sloan Kettering Cancer Center, New York, NY.

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 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.

PMID:
29506079
PMCID:
PMC6136925
DOI:
10.1093/jnci/djy028
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center