The landscape of somatic genetic alterations in breast cancers from atm germline mutation carriers

Britta Weigelt, Rui Bi, Rahul Kumar, Pedro Blecua, Diana L. Mandelker, Felipe C. Geyer, Fresia Pareja, Paul A. James, Fergus J. Couch, Diana M. Eccles, Fiona Blows, Paul Pharoah, Anqi Li, Pier Selenica, Raymond S. Lim, Gowtham Jayakumaran, Nic Waddell, Ronglai Shen, Larry Norton, Hannah Y. WenSimon N. Powell, Nadeem Riaz, Mark E. Robson, Jorge S. Reis-Filho, Georgia Chenevix-Trench

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1030-1034
Number of pages5
JournalJournal of the National Cancer Institute
Issue number9
StatePublished - Sep 1 2018

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


Dive into the research topics of 'The landscape of somatic genetic alterations in breast cancers from atm germline mutation carriers'. Together they form a unique fingerprint.

Cite this