六万女性乳腺癌相关基因致病变异
为了对基因致病变异女性进行乳腺癌风险评定和管理，迫切需要整个人群的癌症易感基因可遗传基因致病变异相关乳腺癌风险数据。
2021年1月20日，国际四大医学期刊之首、美国麻省医学会《新英格兰医学杂志》在线发表美国癌症学会、梅奥医学中心、哈佛大学、波士顿大学、布莱根医院和波士顿妇女医院、罗斯威尔帕克综合癌症中心、康奈尔大学、尔湾加利福尼亚大学、希望之城国家医学中心、南加利福尼亚大学、斯坦福大学、威斯康星大学、新泽西州立大学、弗雷德哈钦森癌症研究中心、华盛顿大学、夏威夷大学、国家环境卫生科学研究所、范德堡大学、犹他大学、宾夕法尼亚大学、德国凯杰、英国牛津大学的研究报告，对美国超过6.4万例女性28个已知癌症相关基因的致病变异进行了分析。
该人群病例对照研究利用定制的多基因扩增子大规模并行测序平台，对美国癌症易感基因携带者联盟3万2247例乳腺癌女性（病例患者）和3万2544例无乳腺癌女性（对照者）28个已知癌症相关基因进行测序，确定可遗传致病变异，并对各个基因致病变异的乳腺癌风险进行评定。
结果，其中12个确定为乳腺癌易感基因，乳腺癌病例患者与对照者相比，致病变异比例：
12个基因：5.03%比1.63%
BRCA1基因：0.85%比0.11%（比值比：7.62，95%置信区间：5.33～11.27，P<0.001）
BRCA2基因：1.29%比0.24%（比值比：5.23，95%置信区间：4.09～6.77，P<0.001）
PALB2基因：0.46%比0.12%（比值比：3.83，95%置信区间：2.68～5.63，P<0.001）
雌激素受体阴性乳腺癌和三阴性乳腺癌病例患者与对照者相比，BARD1、RAD51C、RAD51D基因致病变异比例显著较高。
雌激素受体阳性乳腺癌病例患者与对照者相比，ATM、CDH1、CHEK2基因致病变异比例显著较高。
乳腺癌病例患者与对照者相比，其余16个可能为乳腺癌易感基因的致病变异比例相似，包括NBN基因c.657_661del5致病变异（比值比：0.93，95%置信区间：0.52～1.68）。
因此，该研究提供了美国人群已知乳腺癌相关基因致病变异的乳腺癌风险数据，可为普通人群的癌症检测和筛查提供信息，并提高这些基因可遗传致病变异的临床治疗水平。
对此，加拿大多伦多大学史蒂文·纳罗德教授发表同期评论：哪些基因可遗传乳腺癌？
N Engl J Med. 2021 Jan 20. Online ahead of print.
A Population-Based Study of Genes Previously Implicated in Breast Cancer.
Chunling Hu, Steven N. Hart, Rohan Gnanaolivu, Hongyan Huang, Kun Y. Lee, Jie Na, Chi Gao, Jenna Lilyquist, Siddhartha Yadav, Nicholas J. Boddicker, Raed Samara, Josh Klebba, Christine B. Ambrosone, Hoda Anton-Culver, Paul Auer, Elisa V. Bandera, Leslie Bernstein, Kimberly A. Bertrand, Elizabeth S. Burnside, Brian D. Carter, Heather Eliassen, Susan M. Gapstur, Mia Gaudet, Christopher Haiman, James M. Hodge, David J. Hunter, Eric J. Jacobs, Esther M. John, Charles Kooperberg, Allison W. Kurian, Loic Le Marchand, Sara Lindstroem, Tricia Lindstrom, Huiyan Ma, Susan Neuhausen, Polly A. Newcomb, Katie M. O'Brien, Janet E. Olson, Irene M. Ong, Tuya Pal, Julie R. Palmer, Alpa V. Patel, Sonya Reid, Lynn Rosenberg, Dale P. Sandler, Christopher Scott, Rulla Tamimi, Jack A. Taylor, Amy Trentham-Dietz, Celine M. Vachon, Clarice Weinberg, Song Yao, Argyrios Ziogas, Jeffrey N. Weitzel, David E. Goldgar, Susan M. Domchek, Katherine L. Nathanson, Peter Kraft, Eric C. Polley, Fergus J. Couch.
Mayo Clinic, Rochester, MN; Harvard University T.H. Chan School of Public Health, Boston University, Brigham and Women's Hospital, Boston; Roswell Park Comprehensive Cancer Center, Buffalo; Weill Cornell Medicine, New York, New York; University of California, Irvine; Beckman Research Institute of City of Hope, Duarte; University of Southern California, Los Angeles; Stanford University School of Medicine, Stanford, California; University of Wisconsin-Milwaukee Joseph J. Zilber School of Public Health, Milwaukee; University of Wisconsin-Madison, Madison; State University of New Jersey, New Brunswick; American Cancer Society, Atlanta; Fred Hutchinson Cancer Research Center, University of Washington, Seattle; University of Hawaii Cancer Center, Honolulu; National Institute of Environmental Health Sciences, Durham, NC; Vanderbilt University, Nashville; University of Utah, Salt Lake City; University of Pennsylvania, Philadelphia; Qiagen, Hilden, Germany; University of Oxford, Oxford, United Kingdom.
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.)
DOI: 10.1056/NEJMoa2005936
N Engl J Med. 2021 Jan 20. Online ahead of print.
Which Genes for Hereditary Breast Cancer?
Steven A. Narod.
Women's College Research Institute, Toronto.
DOI: 10.1056/NEJMe2035083