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 firstname.lastname@example.org.
1. Couch FJ, Shimelis H, Hu C, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol 2017;3:1190-1196.
2. Easton DF, Pharoah PDP, Antoniou AC, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 2015;372:2243-2257.
3. 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;110:855-862.
4. 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).
5. Domchek SM, Friebel TM, Singer CF, et al. Association of risk-reducing surgery in BRCA1 or BRCA2 mutation carriers with cancer risk and mortality. JAMA 2010;304:967-975.
6. Tung NM, Garber JE. BRCA1/2 testing: therapeutic implications for breast cancer management. Br J Cancer 2018;119:141-152.
7. Buys SS, Sandbach JF, Gammon A, et al. A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes. Cancer 2017;123:1721-1730.
8. Hauke J, Horvath J, Groß E, et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med 2018;7:1349-1358.
9. Kurian AW, Hughes E, Handorf EA, et al. Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precis Oncol 2017;1:1-12.
10. Tung N, Battelli C, Allen B, et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 2015;121:25-33.
11. Momozawa Y, Iwasaki Y, Parsons MT, et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun 2018;9:4083-4083.
12. Tung N, Lin NU, Kidd J, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol 2016;34:1460-1468.
13. Terry MB, Liao Y, Whittemore AS, et al. 10-Year performance of four models of breast cancer risk: a validation study. Lancet Oncol 2019;20:504-517.
14. US Preventive Services task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA 2019;322:652-665.
15. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology — genetic/familial high-risk assessment: breast, ovarian, and pancreatic. Version 1. 2020 (https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. opens in new tab).
16. King M-C, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA 2014;312:1091-1092.
17. Hu C, Hart SN, Polley EC, et al. Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018;319:2401-2409.
18. Bogdanova N, Feshchenko S, Schürmann P, et al. Nijmegen Breakage Syndrome mutations and risk of breast cancer. Int J Cancer 2008;122:802-806.
19. Borg A, Sandberg T, Nilsson K, et al. High frequency of multiple melanomas and breast and pancreas carcinomas in CDKN2A mutation-positive melanoma families. J Natl Cancer Inst 2000;92:1260-1266.
20. Damiola F, Pertesi M, Oliver J, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a Breast Cancer Family Registry case-control mutation-screening study. Breast Cancer Res 2014;16(3):R58-R58.
21. Goldberg M, Bell K, Aronson M, et al. Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry. J Med Genet 2017;54:742-746.
22. Harkness EF, Barrow E, Newton K, et al. Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J Med Genet 2015;52:553-556.
23. Kiiski JI, Pelttari LM, Khan S, et al. Exome sequencing identifies FANCM as a susceptibility gene for triple-negative breast cancer. Proc Natl Acad Sci U S A 2014;111:15172-15177.
24. Park DJ, Lesueur F, Nguyen-Dumont T, et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet 2012;90:734-739.
25. Park DJ, Tao K, Le Calvez-Kelm F, et al. Rare mutations in RINT1 predispose carriers to breast and Lynch syndrome-spectrum cancers. Cancer Discov 2014;4:804-815.
26. Roberts ME, Jackson SA, Susswein LR, et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 2018;20:1167-1174.
27. Seal S, Thompson D, Renwick A, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet 2006;38:1239-1241.
28. Sun J, Wang Y, Xia Y, et al. Mutations in RECQL gene are associated with predisposition to breast cancer. PLoS Genet 2015;11(5):e1005228-e1005228.
29. Thompson ER, Doyle MA, Ryland GL, et al. Exome sequencing identifies rare deleterious mutations in DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLoS Genet 2012;8(9):e1002894-e1002894.
30. Vijai J, Topka S, Villano D, et al. A recurrent ERCC3 truncating mutation confers moderate risk for breast cancer. Cancer Discov 2016;6:1267-1275.
31. Weitzel JN, Chao EC, Nehoray B, et al. Somatic TP53 variants frequently confound germ-line testing results. Genet Med 2018;20:809-816.
32. Wood SN. Generalized additive models: an introduction with R. New York: Chapman & Hall/CRC Texts in Statistical Science, 2017.
33. Steffen J, Nowakowska D, Niwińska A, et al. Germline mutations 657del5 of the NBS1 gene contribute significantly to the incidence of breast cancer in Central Poland. Int J Cancer 2006;119:472-475.
34. Rusak B, Kluźniak W, Wokołorczyk D, et al. Allelic modification of breast cancer risk in women with an NBN mutation. Breast Cancer Res Treat 2019;178:427-431.
35. Maxwell KN, Wubbenhorst B, D’Andrea K, et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med 2015;17:630-638.
36. Manahan ER, Kuerer HM, Sebastian M, et al. Consensus guidelines on genetic testing for hereditary breast cancer from the American Society of Breast Surgeons. Ann Surg Oncol 2019;26:3025-3031.
37. Yadav S, Hu C, Hart SN, et al. Evaluation of germline genetic testing criteria in a hospital-based series of women with breast cancer. J Clin Oncol 2020;38:1409-1418.
38. National Institute for Health and Care Excellence. Familial breast cancer: classification, care and managing breast cancer and related risks in people with a family history of breast cancer. 2019 (www.nice.org.uk/guidance/CG164. opens in new tab).
39. Couch FJ, Hart SN, Sharma P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 2015;33:304-311.
40. Manchanda R, Patel S, Gordeev VS, et al. Cost-effectiveness of population-based BRCA1, BRCA2, RAD51C, RAD51D, BRIP1, PALB2 mutation testing in unselected general population women. J Natl Cancer Inst 2018;110:714-725.
41. Manchanda R, Lieberman S, Gaba F, Lahad A, Levy-Lahad E. Population screening for inherited predisposition to breast and ovarian cancer. Annu Rev Genomics Hum Genet 2020;21:373-412.
42. LaDuca H, Polley EC, Yussuf A, et al. A clinical guide to hereditary cancer panel testing: evaluation of gene-specific cancer associations and sensitivity of genetic testing criteria in a cohort of 165,000 high-risk patients. Genet Med 2020;22:407-415.
43. Cybulski C, Kluźniak W, Huzarski T, et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol 2015;16:638-644.
44. Yang X, Leslie G, Doroszuk A, et al. Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families. J Clin Oncol 2020;38:674-685.