IFOM ETS - The AIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy.
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA.
Eur J Hum Genet. 2023 May;31(5):578-587. doi: 10.1038/s41431-022-01257-w. Epub 2023 Jan 27.
Evidence from literature, including the BRIDGES study, indicates that germline protein truncating variants (PTVs) in FANCM confer moderately increased risk of ER-negative and triple-negative breast cancer (TNBC), especially for women with a family history of the disease. Association between FANCM missense variants (MVs) and breast cancer risk has been postulated. In this study, we further used the BRIDGES study to test 689 FANCM MVs for association with breast cancer risk, overall and in ER-negative and TNBC subtypes, in 39,885 cases (7566 selected for family history) and 35,271 controls of European ancestry. Sixteen common MVs were tested individually; the remaining rare 673 MVs were tested by burden analyses considering their position and pathogenicity score. We also conducted a meta-analysis of our results and those from published studies. We did not find evidence for association for any of the 16 variants individually tested. The rare MVs were significantly associated with increased risk of ER-negative breast cancer by burden analysis comparing familial cases to controls (OR = 1.48; 95% CI 1.07-2.04; P = 0.017). Higher ORs were found for the subgroup of MVs located in functional domains or predicted to be pathogenic. The meta-analysis indicated that FANCM MVs overall are associated with breast cancer risk (OR = 1.22; 95% CI 1.08-1.38; P = 0.002). Our results support the definition from previous analyses of FANCM as a moderate-risk breast cancer gene and provide evidence that FANCM MVs could be low/moderate risk factors for ER-negative and TNBC subtypes. Further genetic and functional analyses are necessary to clarify better the increased risks due to FANCM MVs.
来自文献的证据,包括 BRIDGES 研究,表明 FANCM 的种系蛋白截断变异(PTVs)赋予 ER-阴性和三阴性乳腺癌(TNBC)的风险适度增加,尤其是对于具有疾病家族史的女性。已经推测 FANCM 错义变异(MVs)与乳腺癌风险之间存在关联。在这项研究中,我们进一步使用 BRIDGES 研究,在 39885 例病例(7566 例因家族史而选择)和 35271 例欧洲血统对照中,针对 ER-阴性和 TNBC 亚型,对 689 个 FANCM MVs 与乳腺癌风险的关联进行了检测,总体上以及 ER-阴性和 TNBC 亚型中。单独测试了 16 个常见的 MVs;剩余的 673 个罕见 MVs 通过考虑其位置和致病性评分的负担分析进行了测试。我们还对我们的结果和已发表研究的结果进行了荟萃分析。我们没有发现任何单独测试的 16 个变体的关联证据。通过对家族病例与对照进行负担分析,罕见 MVs 与 ER-阴性乳腺癌风险显著相关(OR=1.48;95%CI 1.07-2.04;P=0.017)。在位于功能域或预测为致病性的 MVs 的亚组中发现了更高的 OR。荟萃分析表明,FANCM MVs 总体上与乳腺癌风险相关(OR=1.22;95%CI 1.08-1.38;P=0.002)。我们的结果支持先前对 FANCM 作为中度风险乳腺癌基因的分析定义,并提供了证据表明 FANCM MVs 可能是 ER-阴性和 TNBC 亚型的低/中度风险因素。需要进一步的遗传和功能分析来更好地阐明由于 FANCM MVs 而增加的风险。
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