A Population-Based Study of Genes Previously Implicated in Breast Cancer
Chunling Hu1, Steven N Hart1, Rohan Gnanaolivu1
1From 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.).
Germline pathogenic variants in known breast cancer genes like BRCA1 and BRCA2 significantly increase breast cancer risk. This study provides crucial population-based risk estimates for better management of inherited cancer predispositions.
Area of Science:
- Genetics
- Oncology
- Epidemiology
Background:
- Accurate population-based risk estimates for breast cancer associated with germline pathogenic variants are essential for risk assessment and management.
- Understanding the prevalence and impact of inherited cancer-predisposition genes is critical for women's health.
Purpose of the Study:
- To estimate the prevalence and population-based risk of breast cancer associated with germline pathogenic variants in 28 cancer-predisposition genes.
- To inform clinical management strategies for women with inherited predispositions.
Main Methods:
- A population-based case-control study involving 32,247 women with breast cancer and 32,544 controls.
- Sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes.
- Statistical assessment of associations between identified pathogenic variants and breast cancer risk.
Main Results:
- Pathogenic variants in 12 established breast cancer-predisposition genes were found in 5.03% of cases and 1.63% of controls.
- Pathogenic variants in BRCA1 and BRCA2 showed high breast cancer risk (ORs 7.62 and 5.23).
- Variants in PALB2, BARD1, RAD51C, RAD51D, ATM, CDH1, and CHEK2 were associated with varying risks, including specific associations with estrogen receptor-positive/negative and triple-negative breast cancer.
Conclusions:
- This study provides the first U.S. population-based estimates of breast cancer risk associated with germline pathogenic variants in known predisposition genes.
- These findings are vital for improving genetic testing, cancer screening, and clinical management for women with inherited cancer predispositions.
- Pathogenic variants in 16 candidate genes were not associated with increased breast cancer risk in this study.
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