Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer

Fergus J. Couch, Steven N. Hart, Priyanka Sharma, Amanda Ewart Toland, Xianshu Wang, Penelope Miron, Janet E. Olson, Andrew K. Godwin, V. Shane Pankratz, Curtis Olswold, Seth Slettedahl, Emily Hallberg, Lucia Guidugli, Jaime Davila, Matthias W. Beckmann, Wolfgang Janni, Brigitte Rack, Arif B. Ekici, Dennis J. Slamon, Irene KonstantopoulouFlorentia Fostira, Athanassios Vratimos, George Fountzilas, Liisa M. Pelttari, William J. Tapper, Lorraine Durcan, Simon S. Cross, Robert Pilarski, Charles L. Shapiro, Jennifer Klemp, Song Yao, Judy Garber, Angela Cox, Hiltrud Brauch, Christine Ambrosone, Heli Nevanlinna, Drakoulis Yannoukakos, Susan L. Slager, Celine M. Vachon, Diana M. Eccles, Peter A. Fasching

Research output: Contribution to journalArticle

308 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)304-311
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number4
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Couch, F. J., Hart, S. N., Sharma, P., Toland, A. E., Wang, X., Miron, P., Olson, J. E., Godwin, A. K., Pankratz, V. S., Olswold, C., Slettedahl, S., Hallberg, E., Guidugli, L., Davila, J., Beckmann, M. W., Janni, W., Rack, B., Ekici, A. B., Slamon, D. J., ... Fasching, P. A. (2015). Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. Journal of Clinical Oncology, 33(4), 304-311. https://doi.org/10.1200/JCO.2014.57.1414