Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

Fergus J Couch, Hermela Shimelis, Chunling Hu, Steven Hart, Eric Polley, Jie Na, Emily Hallberg, Raymond Moore, Abigail Thomas, Jenna Lilyquist, Bingjian Feng, Rachel McFarland, Tina Pesaran, Robert Huether, Holly LaDuca, Elizabeth C. Chao, David E. Goldgar, Jill S. Dolinsky

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Abstract

Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.

Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.

Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.

Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.

Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.

Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

Original languageEnglish (US)
Pages (from-to)1190-1196
Number of pages7
JournalJAMA oncology
Volume3
Issue number9
DOIs
StatePublished - Sep 1 2017

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Breast Neoplasms
Neoplasm Genes
Genes
Neoplasms
Genetic Testing
Exome
Ovarian Neoplasms
Outcome Assessment (Health Care)
Population

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. / Couch, Fergus J; Shimelis, Hermela; Hu, Chunling; Hart, Steven; Polley, Eric; Na, Jie; Hallberg, Emily; Moore, Raymond; Thomas, Abigail; Lilyquist, Jenna; Feng, Bingjian; McFarland, Rachel; Pesaran, Tina; Huether, Robert; LaDuca, Holly; Chao, Elizabeth C.; Goldgar, David E.; Dolinsky, Jill S.

In: JAMA oncology, Vol. 3, No. 9, 01.09.2017, p. 1190-1196.

Research output: Contribution to journalArticle

Couch, FJ, Shimelis, H, Hu, C, Hart, S, Polley, E, Na, J, Hallberg, E, Moore, R, Thomas, A, Lilyquist, J, Feng, B, McFarland, R, Pesaran, T, Huether, R, LaDuca, H, Chao, EC, Goldgar, DE & Dolinsky, JS 2017, 'Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer', JAMA oncology, vol. 3, no. 9, pp. 1190-1196. https://doi.org/10.1001/jamaoncol.2017.0424
Couch, Fergus J ; Shimelis, Hermela ; Hu, Chunling ; Hart, Steven ; Polley, Eric ; Na, Jie ; Hallberg, Emily ; Moore, Raymond ; Thomas, Abigail ; Lilyquist, Jenna ; Feng, Bingjian ; McFarland, Rachel ; Pesaran, Tina ; Huether, Robert ; LaDuca, Holly ; Chao, Elizabeth C. ; Goldgar, David E. ; Dolinsky, Jill S. / Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer. In: JAMA oncology. 2017 ; Vol. 3, No. 9. pp. 1190-1196.
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abstract = "Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2{\%}. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95{\%} CI, 2.22-3.62), BARD1 (OR, 2.16; 95{\%} CI, 1.31-3.63), CHEK2 (OR, 1.48; 95{\%} CI, 1.31-1.67), PALB2 (OR, 7.46; 95{\%} CI, 5.12-11.19), and RAD51D (OR, 3.07; 95{\%} CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.",
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T1 - Associations Between Cancer Predisposition Testing Panel Genes and Breast Cancer

AU - Couch, Fergus J

AU - Shimelis, Hermela

AU - Hu, Chunling

AU - Hart, Steven

AU - Polley, Eric

AU - Na, Jie

AU - Hallberg, Emily

AU - Moore, Raymond

AU - Thomas, Abigail

AU - Lilyquist, Jenna

AU - Feng, Bingjian

AU - McFarland, Rachel

AU - Pesaran, Tina

AU - Huether, Robert

AU - LaDuca, Holly

AU - Chao, Elizabeth C.

AU - Goldgar, David E.

AU - Dolinsky, Jill S.

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N2 - Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

AB - Importance: Germline pathogenic variants in BRCA1 and BRCA2 predispose to an increased lifetime risk of breast cancer. However, the relevance of germline variants in other genes from multigene hereditary cancer testing panels is not well defined.Objective: To determine the risks of breast cancer associated with germline variants in cancer predisposition genes.Design, Setting, and Participants: A study population of 65 057 patients with breast cancer receiving germline genetic testing of cancer predisposition genes with hereditary cancer multigene panels. Associations between pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes and breast cancer risk were estimated in a case-control analysis of patients with breast cancer and Exome Aggregation Consortium reference controls. The women underwent testing between March 15, 2012, and June 30, 2016.Main Outcomes and Measures: Breast cancer risk conferred by pathogenic variants in non-BRCA1 and non-BRCA2 predisposition genes.Results: The mean (SD) age at diagnosis for the 65 057 women included in the analysis was 48.5 (11.1) years. The frequency of pathogenic variants in 21 panel genes identified in 41 611 consecutively tested white women with breast cancer was estimated at 10.2%. After exclusion of BRCA1, BRCA2, and syndromic breast cancer genes (CDH1, PTEN, and TP53), observed pathogenic variants in 5 of 16 genes were associated with high or moderately increased risks of breast cancer: ATM (OR, 2.78; 95% CI, 2.22-3.62), BARD1 (OR, 2.16; 95% CI, 1.31-3.63), CHEK2 (OR, 1.48; 95% CI, 1.31-1.67), PALB2 (OR, 7.46; 95% CI, 5.12-11.19), and RAD51D (OR, 3.07; 95% CI, 1.21-7.88). Conversely, variants in the BRIP1 and RAD51C ovarian cancer risk genes; the MRE11A, RAD50, and NBN MRN complex genes; the MLH1 and PMS2 mismatch repair genes; and NF1 were not associated with increased risks of breast cancer.Conclusions and Relevance: This study establishes several panel genes as high- and moderate-risk breast cancer genes and provides estimates of breast cancer risk associated with pathogenic variants in these genes among individuals qualifying for clinical genetic testing.

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