基于人群的先前与乳腺癌相关的基因研究。
A Population-Based Study of Genes Previously Implicated in Breast Cancer.
机构信息
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.).
出版信息
N Engl J Med. 2021 Feb 4;384(5):440-451. doi: 10.1056/NEJMoa2005936. Epub 2021 Jan 20.
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 and 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 were associated with a moderate risk (odds ratio, 3.83; 95% CI, 2.68 to 5.63). Pathogenic variants in , , and were associated with increased risks of estrogen receptor-negative breast cancer and triple-negative breast cancer, whereas pathogenic variants in , , and 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 , 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.).
背景
为了进行风险评估和管理，我们迫切需要基于人群的研究来估算与癌症易感基因种系致病性变异相关的乳腺癌风险，这些基因变异存在于具有遗传性致病性变异的女性中。
方法
在一项基于人群的病例对照研究中，我们使用定制的多基因扩增子靶向面板进行测序，以鉴定 28 个癌症易感基因中的种系致病性变异，这些基因来自癌症风险估计相关易感性（CARRIERS）联盟中基于人群的研究中的 32247 名乳腺癌患者（病例患者）和 32544 名未受影响的女性（对照组）。评估了每个基因中的致病性变异与乳腺癌风险之间的关联。
结果
在 5.03%的病例患者和 1.63%的对照组中检测到 12 个已确立的乳腺癌易感基因中的致病性变异。和 中的致病性变异与乳腺癌的高风险相关，比值比分别为 7.62（95%置信区间[CI]，5.33 至 11.27）和 5.23（95%CI，4.09 至 6.77）。中的致病性变异与中度风险相关（比值比，3.83；95%CI，2.68 至 5.63）。中的致病性变异与雌激素受体阴性乳腺癌和三阴性乳腺癌的风险增加相关，而中的致病性变异与雌激素受体阳性乳腺癌的风险增加相关。16 个候选乳腺癌易感基因中的致病性变异，包括 中的 c.657_661del5 创始人致病性变异，与乳腺癌风险增加无关。
结论
本研究提供了美国人群中已知乳腺癌易感基因种系致病性变异与乳腺癌相关性的患病率和风险估计。这些估计可以为癌症检测和筛查提供信息，并为这些基因中具有遗传性致病性变异的普通人群中的女性改善临床管理策略。（由美国国立卫生研究院和乳腺癌研究基金会资助）。
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