Abstract 1225: Rare variants in DNA damage repair genes are associated with male breast cancer predisposition

Abstract

Abstract Male breast cancer accounts for approximately 1% of all breast cancers diagnosed each year in the UK. Germline mutations in DNA damage response genes are known to be associated with many forms of cancer, including breast cancer. In order to identify low frequency male breast cancer predisposition genes, we performed targeted resequencing of more than 300 genes that were selected on the basis of involvement in DNA maintenance and repair pathways. Using a cost-effective protocol based on an automated library preparation method and a multiplexed hybridization enrichment step, we sequenced 1,029 male breast cancer cases from the UK Breast Cancer Now male breast cancer study (MBCS) and 1,254 controls from the MBCS and the ICR1000 UK exome series. Rare variants localising to 19 genes were significantly associated with risk of male breast cancer. Genes with an excess of rare coding mutations included the known breast cancer susceptibility genes BRCA2, CHEK2 and ATM as well as multiple members of the Fanconi anaemia (FA) pathway. Loss of heterozygosity (LOH) affecting the wildtype allele of putative predisposition genes was observed more than 10% of cases with matched tumor samples. In addition to LOH in BRCA2 mutation carries, somatic losses were observed that affected CCNE1, ATM, PALB2, BARD1, CHEK2, POLL and RAD9A. These data represent the largest analysis of rare variants in male breast cancer to date and have enabled the identification of known and putative novel susceptibility genes. Citation Format: Sarah L. Maguire, Katarzyna Tomczyk, Eleni Perrakis, Edward Saunders, Daniel Leongamornlert, ZSofia Kote-Jarai, Rosalind Eeles, Montserrat Garcia-Closas, Paul Pharoah, Douglas Easton, Christopher J. Lord, Alan Ashworth, Anthony Swerdlow, Nick Orr. Rare variants in DNA damage repair genes are associated with male breast cancer predisposition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1225.