在一项基于人群的病例对照研究中，我们在参与CARRIERS（与易感性相关的癌症风险估计，Cancer Risk Estimates Related to Susceptibility）人群研究的32,247例乳腺癌女性患者（病例）和32,544例未患病女性（对照）中，利用基于多基因扩增子的定制基因面板进行了测序，目的是在28个癌症易感基因中识别生殖细胞系致病变异体。我们评估了各基因的致病变异体与乳腺癌风险的关联。
在12个已知的乳腺癌易感基因中，我们检测出5.03%的病例和1.63%的对照有上述基因的致病变异体。BRCA1和BRCA2的致病变异体与乳腺癌的高风险相关，比值比分别为7.62（95% CI，5.33～11.27）和5.23（95% CI，4.09～6.77）。PALB2的致病变异体与中等风险相关（比值比，3.83；95% CI，2.68～5.63）。BARD1、RAD51C和RAD51D的致病变异体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ATM、CDH1和CHEK2的致病变异体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的致病变异体（包括NBN的c.657_661del5始祖致病变异体）与乳腺癌风险增加无关。
本研究提供了在美国人群中与已知乳腺癌易感基因的致病变异体相关的乳腺癌患病率和风险估计值。这些估计值可指导乳腺癌的检查和筛查，并改善一般人群中携带这些基因的遗传性致病变异体的女性的临床管理策略（由美国国立卫生研究院和乳腺癌研究基金会[Breast Cancer Research Foundation]资助）。
Chunling Hu, M.D., Ph.D., Steven N. Hart, Ph.D., Rohan Gnanaolivu, M.S., Hongyan Huang, Ph.D., Kun Y. Lee, Ph.D., Jie Na, M.S., Chi Gao, M.Sc., Jenna Lilyquist, Ph.D., Siddhartha Yadav, M.D., Nicholas J. Boddicker, Ph.D., Raed Samara, Ph.D., Josh Klebba, B.S., Christine B. Ambrosone, Ph.D., Hoda Anton-Culver, Ph.D., Paul Auer, Ph.D., Elisa V. Bandera, Ph.D., Leslie Bernstein, Ph.D., Kimberly A. Bertrand, Sc.D., Elizabeth S. Burnside, M.D., M.P.H., Brian D. Carter, M.P.H., Heather Eliassen, Sc.D., Susan M. Gapstur, Ph.D., Mia Gaudet, Ph.D., Christopher Haiman, Sc.D., James M. Hodge, M.P.H., J.D., David J. Hunter, Sc.D., Eric J. Jacobs, Ph.D., Esther M. John, Ph.D., Charles Kooperberg, Ph.D., Allison W. Kurian, M.D., Loic Le Marchand, M.D., Ph.D., Sara Lindstroem, Ph.D., Tricia Lindstrom, B.S., Huiyan Ma, Ph.D., Susan Neuhausen, Ph.D., Polly A. Newcomb, Ph.D., M.P.H., Katie M. O’Brien, Ph.D., Janet E. Olson, Ph.D., Irene M. Ong, Ph.D., Tuya Pal, M.D., Julie R. Palmer, Sc.D., Alpa V. Patel, Ph.D., Sonya Reid, M.D., Lynn Rosenberg, Sc.D., Dale P. Sandler, Ph.D., Christopher Scott, M.S., Rulla Tamimi, Sc.D., Jack A. Taylor, M.D., Ph.D., Amy Trentham-Dietz, Ph.D., Celine M. Vachon, Ph.D., Clarice Weinberg, Ph.D., Song Yao, Ph.D., Argyrios Ziogas, Ph.D., Jeffrey N. Weitzel, M.D., David E. Goldgar, Ph.D., Susan M. Domchek, M.D., Katherine L. Nathanson, M.D., Peter Kraft, Sc.D., Eric C. Polley, Ph.D., and Fergus J. Couch, Ph.D.
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.). Address reprint requests to Dr. Couch at the Department of Laboratory Medicine and Pathology, Mayo Clinic, Stabile 2-42, 200 First St. SW, Rochester, MN 55905, or at email@example.com.
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