Abstract AS09: Germline mutations in cancer susceptibility genes in BRCA1 and BRCA2 negative families with ovarian and breast cancer
Authors: Norquist B. , Harrell M. , Walsh T. , Mandell J. , Bernards S. , Agnew K. , Lee M. , Pennington K. , King M.C. , Swisher E. 
Published: August 2015

Abstract
Objectives: Germline mutations in cancer susceptibility genes other than BRCA1 and BRCA2 (BRCA1/2) are found in approximately 6% of women with ovarian, fallopian tube, or primary peritoneal cancer. Our objective was to sequence BRCA1/2-negative ovarian cancer patients with a family history of ovarian or breast cancer to identify inherited mutations that may explain the familial risk.
Methods: We used a targeted capture, massively parallel sequencing test called BROCA on ovarian cancer probands with a family history of ovarian or breast cancer, or a personal history of breast cancer. BROCA testing included all known breast and ovarian cancer genes. Only clear loss of function mutations were included. 118 probands were ascertained from a gynecologic oncology tissue bank or outside referrals and provided informed consent. A family history of ovarian cancer was defined as having a first or second degree relative with ovarian cancer. A family history of breast cancer was defined as having a first or second degree relative with pre-menopausal breast cancer, or 2 or more regardless of menopausal status. Subjects were only included in one category.
Results: Of 118 ovarian cancer probands, 22 (18.6%) were found to carry deleterious mutations in non-BRCA1/2 cancer susceptibility genes. 8/29 (27.6%) ovarian cancer patients with a personal history of breast cancer had mutations in 7 genes (2 CHEK2, 2 RAD51D, 1 BRIP1, 1 TP53, 1 ATM, and one with both PALB2 and PMS2). This included mutations found in 2/5 (40%) who also had a family history of ovarian cancer and 4/10 (40%) who also had a family history of breast cancer. 38 patients had a family history of ovarian cancer with no personal history of breast cancer; 9/38 (23.7%) had mutations in 5 genes (3 BRIP1, 3 RAD51C, 1 RAD51D, 1 TP53, and 1 ATM). Finally, 5/51 (9.8%) ovarian cancer patients with a family history of breast cancer and no personal history of breast cancer had mutations in 5 genes (1 MSH6, 1 FAM175A, 1 NBN, 1 PALB2, and 1 CHEK2).
Conclusions: Germline mutations in DNA-repair genes are present in a substantial fraction of BRCA1/2-negative ovarian cancer patients with a personal or family history suggestive of inherited disease. These women may benefit from multiplex gene testing. The detection of inherited mutations in these women may be useful to identify the risk of other cancers, to inform family members of possible risk, and to direct therapy by suggesting candidates for PARP inhibitor therapy.
Citation Format: B. Norquist, M. Harrell, T. Walsh, J. Mandell, S. Bernards, K. Agnew, M. Lee, K. Pennington, M.C. King, E. Swisher. Germline mutations in cancer susceptibility genes in BRCA1 and BRCA2 negative families with ovarian and breast cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS09.