Joo Jihoon E, Dowty James G, Milne Roger L, Wong Ee Ming, Dugué Pierre-Antoine, English Dallas, Hopper John L, Goldgar David E, Giles Graham G, Southey Melissa C
Department of Pathology, The University of Melbourne, Melbourne, VIC, 3010, Australia.
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, 3168, Australia.
Nat Commun. 2018 Feb 28;9(1):867. doi: 10.1038/s41467-018-03058-6.
Mendelian-like inheritance of germline DNA methylation in cancer susceptibility genes has been previously reported. We aimed to scan the genome for heritable methylation marks associated with breast cancer susceptibility by studying 25 Australian multiple-case breast cancer families. Here we report genome-wide DNA methylation measured in 210 peripheral blood DNA samples provided by family members using the Infinium HumanMethylation450. We develop and apply a new statistical method to identify heritable methylation marks based on complex segregation analysis. We estimate carrier probabilities for the 1000 most heritable methylation marks based on family structure, and we use Cox proportional hazards survival analysis to identify 24 methylation marks with corresponding carrier probabilities significantly associated with breast cancer. We replicate an association with breast cancer risk for four of the 24 marks using an independent nested case-control study. Here, we report a novel approach for identifying heritable DNA methylation marks associated with breast cancer risk.
此前已有报道称，癌症易感基因中的种系DNA甲基化呈现孟德尔式遗传。我们旨在通过研究25个澳大利亚多病例乳腺癌家族，扫描基因组以寻找与乳腺癌易感性相关的可遗传甲基化标记。在此，我们报告了使用Infinium HumanMethylation450对家庭成员提供的210份外周血DNA样本进行的全基因组DNA甲基化测量。我们开发并应用了一种新的统计方法，基于复杂分离分析来识别可遗传的甲基化标记。我们根据家族结构估计了1000个最具遗传性的甲基化标记的携带概率，并使用Cox比例风险生存分析来识别24个甲基化标记，其相应的携带概率与乳腺癌显著相关。我们使用独立的巢式病例对照研究对这24个标记中的4个与乳腺癌风险的关联进行了重复验证。在此，我们报告了一种识别与乳腺癌风险相关的可遗传DNA甲基化标记的新方法。
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