Estimates for inherited mutations in breast cancer susceptibility genes among triple-negative breast cancer patients. F. Couch1, S. N. Hart1, P. Sharma2, A. Ewart Toland3, X. Wang1, P. Miron4, J. E. Olson1, A. Godwin2, V. S. Pankratz1, C. Olswold1, M. W. Beckmann5, W. Janni6, B. Rack7, A. Ekici8, D. J. Slamon9, I. Konstantopoulou10, F. Fostira10, G. Fountzilas11, L. Pelttari12, S. Yao13, J. Garber4, A. Cox14, H. Brauch15, C. Ambrosone13, H. Nevanlinna12, D. Yannoukakos10, S. L. Slager1, C. M. Vachon1, D. M. Eccles16, P. A. Fasching5 1) Prof/Dept Lab Med, Mayo Clinic Col Med, Rochester, MN; 2) Department of Medicine, University of Kansas Medical Center, Kansas City, KS; 3) Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH; 4) Dana Farber Cancer Institute, Boston, MA; 5) Department of Gynecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany; 6) Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm, Germany; 7) Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, Campus Innenstadt, Munich, Germany; 8) Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany; 9) University of California at Los Angeles, David Geffen School of Medicine, Department of Medicine, Division Hematology/Oncology, Los Angeles, CA; 10) National Centre for Scientific Research "Demokritos", Athens, Greece; 11) Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki School of Medicine, Greece; 12) Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; 13) Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY; 14) Department of Neuroscience, University of Sheffield, Sheffield, UK; 15) Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; 16) Faculty of Medicine, University of Southampton, Southampton, UK.

   Guidelines recommend germline mutation testing of breast cancer predisposition genes in triple negative (TN) breast cancer cases with a family history of breast or ovarian cancer or when diagnosed under age 60. However, the prevalence of mutations in these genes among TN cases unselected for family history of breast or ovarian cancer is not known. To assess the frequency of mutations in 16 predisposition genes in TN cases we screened a large cohort of 1824 TN patients unselected for family history of breast or ovarian cancer from 12 centers for mutations using a panel-based sequencing approach. Deleterious mutations were identified in 15% of TN patients: 8.5% had BRCA1, 2.7% had BRCA2, and 3.6% had mutations in 12 other genes. Mutations in non-BRCA1/2 genes encoding proteins implicated in homologous recombination repair of DNA double strand breaks were detected at the same frequency as in breast cancer families. TN cases with mutations were diagnosed at an earlier age than non-mutated cases, although 10% of TN cases diagnosed at 60 years and 5% with no family history of cancer were also found to carry likely mutations. Frequency estimates for mutations in the predisposition genes based on age of diagnosis and family history of cancer were also developed. These will allow for selection of TN patients most likely to carry mutations in predisposition genes.

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