Multicenter Study

. 2021 Feb 4;384(5):440-451.

doi: 10.1056/NEJMoa2005936. Epub 2021 Jan 20.

A Population-Based Study of Genes Previously Implicated in Breast Cancer

Chunling Hu¹, Steven N Hart¹, Rohan Gnanaolivu¹, Hongyan Huang¹, Kun Y Lee¹, Jie Na¹, Chi Gao¹, Jenna Lilyquist¹, Siddhartha Yadav¹, Nicholas J Boddicker¹, Raed Samara¹, Josh Klebba¹, Christine B Ambrosone¹, Hoda Anton-Culver¹, Paul Auer¹, Elisa V Bandera¹, Leslie Bernstein¹, Kimberly A Bertrand¹, Elizabeth S Burnside¹, Brian D Carter¹, Heather Eliassen¹, Susan M Gapstur¹, Mia Gaudet¹, Christopher Haiman¹, James M Hodge¹, David J Hunter¹, Eric J Jacobs¹, Esther M John¹, Charles Kooperberg¹, Allison W Kurian¹, Loic Le Marchand¹, Sara Lindstroem¹, Tricia Lindstrom¹, Huiyan Ma¹, Susan Neuhausen¹, Polly A Newcomb¹, Katie M O'Brien¹, Janet E Olson¹, Irene M Ong¹, Tuya Pal¹, Julie R Palmer¹, Alpa V Patel¹, Sonya Reid¹, Lynn Rosenberg¹, Dale P Sandler¹, Christopher Scott¹, Rulla Tamimi¹, Jack A Taylor¹, Amy Trentham-Dietz¹, Celine M Vachon¹, Clarice Weinberg¹, Song Yao¹, Argyrios Ziogas¹, Jeffrey N Weitzel¹, David E Goldgar¹, Susan M Domchek¹, Katherine L Nathanson¹, Peter Kraft¹, Eric C Polley¹, Fergus J Couch¹

Affiliations

Affiliation

¹ From Mayo Clinic, Rochester, MN (C. Hu, S.N.H., R.G., K.Y.L., J.N., J.L., S. Yadav, N.J.B., T.L., J.E.O., C.S., C.M.V., E.C.P., F.J.C.); Harvard University T.H. Chan School of Public Health (H.H., C.G., D.J.H., P.K.), Slone Epidemiology Center at Boston University (K.A.B., J.R.P., L.R.), and Brigham and Women's Hospital (H.E.) - all in Boston; Qiagen, Hilden, Germany (R.S., J.K.); Roswell Park Comprehensive Cancer Center, Buffalo (C.B.A., S. Yao), and Weill Cornell Medicine, New York (R.T.) - both in New York; the University of California, Irvine (H.A.-C., A.Z.), Beckman Research Institute of City of Hope, Duarte (L.B., H.M., S.N., J.N.W.), Keck School of Medicine, University of Southern California, Los Angeles (C. Haiman), and Stanford University School of Medicine, Stanford (E.M.J., A.W.K.) - all in California; the University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee (P.A.), and the University of Wisconsin-Madison, Madison (E.S.B., I.M.O., A.T.-D.); the Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick (E.V.B.); the Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta (B.D.C., S.M.G., M.G., J.M.H., E.J.J., A.V.P.); the University of Oxford, Oxford, United Kingdom (D.J.H.); the Fred Hutchinson Cancer Research Center (C.K., P.A.N.) and the Department of Epidemiology, University of Washington (S.L.) - both in Seattle; the Epidemiology Program, University of Hawaii Cancer Center, Honolulu (L.L.M.); the National Institute of Environmental Health Sciences, Durham, NC (K.M.O., D.P.S., J.A.T., C.W.); Vanderbilt University, Nashville (T.P., S.R.); the University of Utah, Salt Lake City (D.E.G.); and the Department of Medicine and the Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.M.D., K.L.N.).

PMID: 33471974
PMCID: PMC8127622
DOI: 10.1056/NEJMoa2005936

Multicenter Study

A Population-Based Study of Genes Previously Implicated in Breast Cancer

Chunling Hu et al. N Engl J Med. 2021.

. 2021 Feb 4;384(5):440-451.

doi: 10.1056/NEJMoa2005936. Epub 2021 Jan 20.

Authors

Affiliation

¹ From Mayo Clinic, Rochester, MN (C. Hu, S.N.H., R.G., K.Y.L., J.N., J.L., S. Yadav, N.J.B., T.L., J.E.O., C.S., C.M.V., E.C.P., F.J.C.); Harvard University T.H. Chan School of Public Health (H.H., C.G., D.J.H., P.K.), Slone Epidemiology Center at Boston University (K.A.B., J.R.P., L.R.), and Brigham and Women's Hospital (H.E.) - all in Boston; Qiagen, Hilden, Germany (R.S., J.K.); Roswell Park Comprehensive Cancer Center, Buffalo (C.B.A., S. Yao), and Weill Cornell Medicine, New York (R.T.) - both in New York; the University of California, Irvine (H.A.-C., A.Z.), Beckman Research Institute of City of Hope, Duarte (L.B., H.M., S.N., J.N.W.), Keck School of Medicine, University of Southern California, Los Angeles (C. Haiman), and Stanford University School of Medicine, Stanford (E.M.J., A.W.K.) - all in California; the University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee (P.A.), and the University of Wisconsin-Madison, Madison (E.S.B., I.M.O., A.T.-D.); the Cancer Prevention and Control Program, Rutgers Cancer Institute of New Jersey, State University of New Jersey, New Brunswick (E.V.B.); the Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta (B.D.C., S.M.G., M.G., J.M.H., E.J.J., A.V.P.); the University of Oxford, Oxford, United Kingdom (D.J.H.); the Fred Hutchinson Cancer Research Center (C.K., P.A.N.) and the Department of Epidemiology, University of Washington (S.L.) - both in Seattle; the Epidemiology Program, University of Hawaii Cancer Center, Honolulu (L.L.M.); the National Institute of Environmental Health Sciences, Durham, NC (K.M.O., D.P.S., J.A.T., C.W.); Vanderbilt University, Nashville (T.P., S.R.); the University of Utah, Salt Lake City (D.E.G.); and the Department of Medicine and the Basser Center for BRCA, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (S.M.D., K.L.N.).

PMID: 33471974
PMCID: PMC8127622
DOI: 10.1056/NEJMoa2005936

Abstract

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Results: Pathogenic variants in 12 established breast cancer-predisposition genes were detected in 5.03% of case patients and in 1.63% of controls. Pathogenic variants in BRCA1 and BRCA2 were associated with a high risk of breast cancer, with odds ratios of 7.62 (95% confidence interval [CI], 5.33 to 11.27) and 5.23 (95% CI, 4.09 to 6.77), respectively. Pathogenic variants in PALB2 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in BARD1, RAD51C, and RAD51D were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in ATM, CDH1, and CHEK2 were associated with an increased risk of estrogen receptor-positive breast cancer. Pathogenic variants in 16 candidate breast cancer-predisposition genes, including the c.657_661del5 founder pathogenic variant in NBN, were not associated with an increased risk of breast cancer.

Conclusions: This study provides estimates of the prevalence and risk of breast cancer associated with pathogenic variants in known breast cancer-predisposition genes in the U.S. population. These estimates can inform cancer testing and screening and improve clinical management strategies for women in the general population with inherited pathogenic variants in these genes. (Funded by the National Institutes of Health and the Breast Cancer Research Foundation.).

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Figures

**Figure 1.. Population-Based Lifetime Absolute Risk of Breast Cancer Development According to Age and the Commonly Mutated Genes *ATM*, *BRCA1*, *BRCA2*, *CHEK2*, and *PALB2*.**
The Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium studies that were included in the analysis of the absolute risk of breast cancer among pathogenic-variant carriers were the Cancer Prevention Study II, the Cancer Prevention Study 3, the California Teachers’ Study, the Mayo Clinic Breast Cancer Study, the Multiethnic Cohort Study, the Mayo Mammography Health Study, the Nurses’ Health Study, the Nurses’ Health Study II, the Women’s Circle of Health Study, the Women’s Health Initiative, and the Wisconsin Women’s Health Study. The analysis in the general population was performed with the use of age-specific breast cancer incidence data (restricted to non-Hispanic Whites) from the Surveillance, Epidemiology, and End Results 21 registries.

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Comment in

Which Genes for Hereditary Breast Cancer?
Narod SA. Narod SA. N Engl J Med. 2021 Feb 4;384(5):471-473. doi: 10.1056/NEJMe2035083. Epub 2021 Jan 20. N Engl J Med. 2021. PMID: 33471975 No abstract available.
The ten genes for breast (and ovarian) cancer susceptibility.
Foulkes WD. Foulkes WD. Nat Rev Clin Oncol. 2021 May;18(5):259-260. doi: 10.1038/s41571-021-00491-3. Nat Rev Clin Oncol. 2021. PMID: 33692540 No abstract available.

References

1. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017;3:1190–6. - PMC - PubMed
1. Easton DF, Pharoah PDP, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl Med 2015;372:2243–57. - PMC - PubMed
1. Shimelis H, LaDuca H, Hu C, et al. Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst 2018;110: 855–62. - PMC - PubMed
1. Palmer JR, Polley EC, Hu C, et al. Contribution of germline predisposition gene mutations to breast cancer risk in African American women. J Natl Cancer Inst 2020. May 19 (Epub ahead of print). - PMC - PubMed
1. Domchek SM, Friebel TM, Singr CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:?967–75. - PMC - PubMed

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A Population-Based Study of Genes Previously Implicated in Breast Cancer

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A Population-Based Study of Genes Previously Implicated in Breast Cancer

Authors

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Abstract

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Medical

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