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Medline ® Abstract for Reference 11

of 'Prevalence of BRCA1 and BRCA2 mutations and associated cancer risks'

Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer.
Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, Olson JE, Godwin AK, Pankratz VS, Olswold C, Slettedahl S, Hallberg E, Guidugli L, Davila JI, Beckmann MW, Janni W, Rack B, Ekici AB, Slamon DJ, Konstantopoulou I, Fostira F, Vratimos A, Fountzilas G, Pelttari LM, Tapper WJ, Durcan L, Cross SS, Pilarski R, Shapiro CL, Klemp J, Yao S, Garber J, Cox A, Brauch H, Ambrosone C, Nevanlinna H, Yannoukakos D, Slager SL, Vachon CM, Eccles DM, Fasching PA
J Clin Oncol. 2015 Feb;33(4):304-11. Epub 2014 Dec 1.
PURPOSE: Recent advances in DNA sequencing have led to the development of breast cancer susceptibility gene panels for germline genetic testing of patients. We assessed the frequency of mutations in 17 predisposition genes, including BRCA1 and BRCA2, in a large cohort of patients with triple-negative breast cancer (TNBC) unselected for family history of breast or ovarian cancer to determine the utility of germline genetic testing for those with TNBC.
PATIENTS AND METHODS: Patients with TNBC (N = 1,824) unselected for family history of breast or ovarian cancer were recruited through 12 studies, and germline DNA was sequenced to identify mutations.
RESULTS: Deleterious mutations were identified in 14.6% of all patients. Of these, 11.2% had mutations in the BRCA1 (8.5%) and BRCA2 (2.7%) genes. Deleterious mutations in 15 other predisposition genes were detected in 3.7% of patients, with the majority observed in genes involved in homologous recombination, including PALB2 (1.2%) and BARD1, RAD51D, RAD51C, and BRIP1 (0.3% to 0.5%). Patients with TNBC with mutations were diagnosed at an earlier age (P<.001) and had higher-grade tumors (P = .01) than those without mutations.
CONCLUSION: Deleterious mutations in predisposition genes are present at high frequency in patients with TNBC unselected for family history of cancer. Mutation prevalence estimates suggest that patients with TNBC, regardless of age at diagnosis or family history of cancer, should be considered for germline genetic testing of BRCA1 and BRCA2. Although mutations in other predisposition genes are observed among patients with TNBC, better cancer risk estimates are needed before these mutations are used for clinical risk assessment in relatives.
Fergus J. Couch, Steven N. Hart, Xianshu Wang, Janet E. Olson, Vernon S. Pankratz, Curtis Olswold, Seth Slettedahl, Emily Hallberg, Lucia Guidugli, Jaime Davila, Susan L. Slager, and Celine M. Vachon, Mayo Clinic, Rochester, MN; Priyanka Sharma, Andrew K. Godwin, and Jennifer Klemp, University of Kansas Medical Center, Kansas City, KS; Amanda Ewart Toland, Robert Pilarski, and Charles L. Shapiro, Ohio State University, Columbus, OH; Penelope Miron and Judy Garber, Dana-Farber Cancer Institute, Boston, MA; Matthias W. Beckmann, Arif B. Ekici, and Peter A. Fasching, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen; Wolfgang Janni, University Hospital Ulm, Ulm; Brigitte Rack, Ludwig-Maximilians University Munich, Munich; Hiltrud Brauch, Margarete Fischer-Bosch Institute of Clinical Pharmacology, University of Tubingen, Stuttgart, and German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Dennis J. Slamon and Peter A. Fasching, University of California, Los Angeles, Los Angeles, CA; Irene Konstantopoulou, Florentia Fostira, Athanassios Vratimos, and Drakoulis Yannoukakos, National Centre for Scientific Research "Demokritos," Athens; George Fountzilas, "Papageorgiou" Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; Liisa M. Pelttari and Heli Nevanlinna, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; William J. Tapper, Lorraine Durcan, and Diana M. Eccles, University of Southampton, Southampton; Simon S. Cross and Angela Cox, University of Sheffield, Sheffield, United Kingdom; and Song Yao and Christine Ambrosone, Roswell Park Cancer Institute, Buffalo, NY. couch.fergus@mayo.edu.