Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing

Hermela Shimelis, Holly LaDuca, Chunling Hu, Steven Hart, Jie Na, Abigail Thomas, Margaret Akinhanmi, Raymond M. Moore, Hiltrud Brauch, Angela Cox, Diana M. Eccles, Amanda Ewart-Toland, Peter A. Fasching, Florentia Fostira, Judy Garber, Andrew K. Godwin, Irene Konstantopoulou, Heli Nevanlinna, Priyanka Sharma, Drakoulis YannoukakosSong Yao, Bing Jian Feng, Brigette Tippin Davis, Jenna Lilyquist, Tina Pesaran, David E. Goldgar, Eric Polley, Jill S. Dolinsky, Fergus J Couch

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Abstract

Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.

Original languageEnglish (US)
Pages (from-to)855-862
Number of pages8
JournalJournal of the National Cancer Institute
Volume110
Issue number8
DOIs
StatePublished - Jan 1 2018

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Triple Negative Breast Neoplasms
Neoplasm Genes
Odds Ratio
Neoplasms
Breast Neoplasms
Mutation
Genes
Risk Management
Genetic Testing
Progesterone Receptors
Epidermal Growth Factor Receptor
Estrogen Receptors
African Americans
Research
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. / Shimelis, Hermela; LaDuca, Holly; Hu, Chunling; Hart, Steven; Na, Jie; Thomas, Abigail; Akinhanmi, Margaret; Moore, Raymond M.; Brauch, Hiltrud; Cox, Angela; Eccles, Diana M.; Ewart-Toland, Amanda; Fasching, Peter A.; Fostira, Florentia; Garber, Judy; Godwin, Andrew K.; Konstantopoulou, Irene; Nevanlinna, Heli; Sharma, Priyanka; Yannoukakos, Drakoulis; Yao, Song; Feng, Bing Jian; Davis, Brigette Tippin; Lilyquist, Jenna; Pesaran, Tina; Goldgar, David E.; Polley, Eric; Dolinsky, Jill S.; Couch, Fergus J.

In: Journal of the National Cancer Institute, Vol. 110, No. 8, 01.01.2018, p. 855-862.

Research output: Contribution to journalArticle

Shimelis, H, LaDuca, H, Hu, C, Hart, S, Na, J, Thomas, A, Akinhanmi, M, Moore, RM, Brauch, H, Cox, A, Eccles, DM, Ewart-Toland, A, Fasching, PA, Fostira, F, Garber, J, Godwin, AK, Konstantopoulou, I, Nevanlinna, H, Sharma, P, Yannoukakos, D, Yao, S, Feng, BJ, Davis, BT, Lilyquist, J, Pesaran, T, Goldgar, DE, Polley, E, Dolinsky, JS & Couch, FJ 2018, 'Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing', Journal of the National Cancer Institute, vol. 110, no. 8, pp. 855-862. https://doi.org/10.1093/jnci/djy106
Shimelis, Hermela ; LaDuca, Holly ; Hu, Chunling ; Hart, Steven ; Na, Jie ; Thomas, Abigail ; Akinhanmi, Margaret ; Moore, Raymond M. ; Brauch, Hiltrud ; Cox, Angela ; Eccles, Diana M. ; Ewart-Toland, Amanda ; Fasching, Peter A. ; Fostira, Florentia ; Garber, Judy ; Godwin, Andrew K. ; Konstantopoulou, Irene ; Nevanlinna, Heli ; Sharma, Priyanka ; Yannoukakos, Drakoulis ; Yao, Song ; Feng, Bing Jian ; Davis, Brigette Tippin ; Lilyquist, Jenna ; Pesaran, Tina ; Goldgar, David E. ; Polley, Eric ; Dolinsky, Jill S. ; Couch, Fergus J. / Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. In: Journal of the National Cancer Institute. 2018 ; Vol. 110, No. 8. pp. 855-862.
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title = "Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing",
abstract = "Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20{\%} lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0{\%} (3.7{\%} non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.",
author = "Hermela Shimelis and Holly LaDuca and Chunling Hu and Steven Hart and Jie Na and Abigail Thomas and Margaret Akinhanmi and Moore, {Raymond M.} and Hiltrud Brauch and Angela Cox and Eccles, {Diana M.} and Amanda Ewart-Toland and Fasching, {Peter A.} and Florentia Fostira and Judy Garber and Godwin, {Andrew K.} and Irene Konstantopoulou and Heli Nevanlinna and Priyanka Sharma and Drakoulis Yannoukakos and Song Yao and Feng, {Bing Jian} and Davis, {Brigette Tippin} and Jenna Lilyquist and Tina Pesaran and Goldgar, {David E.} and Eric Polley and Dolinsky, {Jill S.} and Couch, {Fergus J}",
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T1 - Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing

AU - Shimelis, Hermela

AU - LaDuca, Holly

AU - Hu, Chunling

AU - Hart, Steven

AU - Na, Jie

AU - Thomas, Abigail

AU - Akinhanmi, Margaret

AU - Moore, Raymond M.

AU - Brauch, Hiltrud

AU - Cox, Angela

AU - Eccles, Diana M.

AU - Ewart-Toland, Amanda

AU - Fasching, Peter A.

AU - Fostira, Florentia

AU - Garber, Judy

AU - Godwin, Andrew K.

AU - Konstantopoulou, Irene

AU - Nevanlinna, Heli

AU - Sharma, Priyanka

AU - Yannoukakos, Drakoulis

AU - Yao, Song

AU - Feng, Bing Jian

AU - Davis, Brigette Tippin

AU - Lilyquist, Jenna

AU - Pesaran, Tina

AU - Goldgar, David E.

AU - Polley, Eric

AU - Dolinsky, Jill S.

AU - Couch, Fergus J

PY - 2018/1/1

Y1 - 2018/1/1

N2 - Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.

AB - Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.

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