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 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

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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

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Triple Negative Breast Neoplasms
Neoplasm Genes
Breast Neoplasms
Mutation
Genetic Testing
BRCA2 Gene
Ovarian Neoplasms
Genes
Neoplasms
BRCA1 Gene
Homologous Recombination
Mutation Rate
DNA Sequence Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. / Couch, Fergus J; Hart, Steven; Sharma, Priyanka; Toland, Amanda Ewart; Wang, Xianshu; Miron, Penelope; Olson, Janet E; Godwin, Andrew K.; Pankratz, V. Shane; Olswold, Curtis; Slettedahl, Seth; Hallberg, Emily; Guidugli, Lucia; Davila, Jaime; Beckmann, Matthias W.; Janni, Wolfgang; Rack, Brigitte; Ekici, Arif B.; Slamon, Dennis J.; Konstantopoulou, Irene; Fostira, Florentia; Vratimos, Athanassios; Fountzilas, George; Pelttari, Liisa M.; Tapper, William J.; Durcan, Lorraine; Cross, Simon S.; Pilarski, Robert; Shapiro, Charles L.; Klemp, Jennifer; Yao, Song; Garber, Judy; Cox, Angela; Brauch, Hiltrud; Ambrosone, Christine; Nevanlinna, Heli; Yannoukakos, Drakoulis; Slager, Susan L; Vachon, Celine M; Eccles, Diana M.; Fasching, Peter A.

In: Journal of Clinical Oncology, Vol. 33, No. 4, 01.02.2015, p. 304-311.

Research output: Contribution to journalArticle

Couch, FJ, Hart, S, Sharma, P, Toland, AE, Wang, X, Miron, P, Olson, JE, Godwin, AK, Pankratz, VS, Olswold, C, Slettedahl, S, Hallberg, E, Guidugli, L, Davila, J, 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 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, vol. 33, no. 4, pp. 304-311. https://doi.org/10.1200/JCO.2014.57.1414
Couch, Fergus J ; Hart, Steven ; Sharma, Priyanka ; Toland, Amanda Ewart ; Wang, Xianshu ; Miron, Penelope ; Olson, Janet E ; Godwin, Andrew K. ; Pankratz, V. Shane ; Olswold, Curtis ; Slettedahl, Seth ; Hallberg, Emily ; Guidugli, Lucia ; Davila, Jaime ; Beckmann, Matthias W. ; Janni, Wolfgang ; Rack, Brigitte ; Ekici, Arif B. ; Slamon, Dennis J. ; Konstantopoulou, Irene ; Fostira, Florentia ; Vratimos, Athanassios ; Fountzilas, George ; Pelttari, Liisa M. ; Tapper, William J. ; Durcan, Lorraine ; Cross, Simon S. ; Pilarski, Robert ; Shapiro, Charles L. ; Klemp, Jennifer ; Yao, Song ; Garber, Judy ; Cox, Angela ; Brauch, Hiltrud ; Ambrosone, Christine ; Nevanlinna, Heli ; Yannoukakos, Drakoulis ; Slager, Susan L ; Vachon, Celine M ; Eccles, Diana M. ; Fasching, Peter A. / Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 4. pp. 304-311.
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title = "Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer",
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.",
author = "Couch, {Fergus J} and Steven Hart and Priyanka Sharma and Toland, {Amanda Ewart} and Xianshu Wang and Penelope Miron and Olson, {Janet E} and Godwin, {Andrew K.} and Pankratz, {V. Shane} and Curtis Olswold and Seth Slettedahl and Emily Hallberg and Lucia Guidugli and Jaime Davila and Beckmann, {Matthias W.} and Wolfgang Janni and Brigitte Rack and Ekici, {Arif B.} and Slamon, {Dennis J.} and Irene Konstantopoulou and Florentia Fostira and Athanassios Vratimos and George Fountzilas and Pelttari, {Liisa M.} and Tapper, {William J.} and Lorraine Durcan and Cross, {Simon S.} and Robert Pilarski and Shapiro, {Charles L.} and Jennifer Klemp and Song Yao and Judy Garber and Angela Cox and Hiltrud Brauch and Christine Ambrosone and Heli Nevanlinna and Drakoulis Yannoukakos and Slager, {Susan L} and Vachon, {Celine M} and Eccles, {Diana M.} and Fasching, {Peter A.}",
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TY - JOUR

T1 - Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer

AU - Couch, Fergus J

AU - Hart, Steven

AU - Sharma, Priyanka

AU - Toland, Amanda Ewart

AU - Wang, Xianshu

AU - Miron, Penelope

AU - Olson, Janet E

AU - Godwin, Andrew K.

AU - Pankratz, V. Shane

AU - Olswold, Curtis

AU - Slettedahl, Seth

AU - Hallberg, Emily

AU - Guidugli, Lucia

AU - Davila, Jaime

AU - Beckmann, Matthias W.

AU - Janni, Wolfgang

AU - Rack, Brigitte

AU - Ekici, Arif B.

AU - Slamon, Dennis J.

AU - Konstantopoulou, Irene

AU - Fostira, Florentia

AU - Vratimos, Athanassios

AU - Fountzilas, George

AU - Pelttari, Liisa M.

AU - Tapper, William J.

AU - Durcan, Lorraine

AU - Cross, Simon S.

AU - Pilarski, Robert

AU - Shapiro, Charles L.

AU - Klemp, Jennifer

AU - Yao, Song

AU - Garber, Judy

AU - Cox, Angela

AU - Brauch, Hiltrud

AU - Ambrosone, Christine

AU - Nevanlinna, Heli

AU - Yannoukakos, Drakoulis

AU - Slager, Susan L

AU - Vachon, Celine M

AU - Eccles, Diana M.

AU - Fasching, Peter A.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

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U2 - 10.1200/JCO.2014.57.1414

DO - 10.1200/JCO.2014.57.1414

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JO - Journal of Clinical Oncology

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