Yu Chenglong, Wong Ee Ming, Joo Jihoon Eric, Hodge Allison M, Makalic Enes, Schmidt Daniel, Buchanan Daniel D, Severi Gianluca, Hopper John L, English Dallas R, Giles Graham G, Southey Melissa C, Dugué Pierre-Antoine
Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
Department of Clinical Pathology, Melbourne Medical School, The University of Melbourne, Parkville, VIC 3010, Australia.
Cancers (Basel). 2021 Apr 14;13(8):1881. doi: 10.3390/cancers13081881.
To investigate age- and sex-specific DNA methylation alterations related to cancer risk and survival, we used matched case-control studies of colorectal ( = 835), gastric ( = 170), kidney ( = 143), lung ( = 332), prostate ( = 869) and urothelial ( = 428) cancers, and mature B-cell lymphoma ( = 438). Linear mixed-effects models were conducted to identify age-, sex- and age-by-sex-associated methylation markers using a discovery (controls)-replication (cases) strategy. Replication was further examined using summary statistics from Generation Scotland (GS). Associations between replicated markers and risk of and survival from cancer were assessed using conditional logistic regression and Cox models (hazard ratios (HR)), respectively. We found 32,659, 23,141 and 48 CpGs with replicated associations for age, sex and age-by-sex, respectively. The replication rates for these CpGs using GS summary data were 94%, 86% and 91%, respectively. Significant associations for cancer risk and survival were identified at some individual age-related CpGs. Opposite to previous findings using epigenetic clocks, there was a strong negative trend in the association between epigenetic drift and risk of colorectal cancer. Methylation at two CpGs overlapping and genes was associated with survival of overall (HR = 0.91, = 7.7 × 10) and colorectal (HR = 1.52, = 1.8 × 10) cancer, respectively, with significant age-by-sex interaction. Our results may provide markers for cancer early detection and prognosis prediction.
为了研究与癌症风险和生存相关的年龄和性别特异性DNA甲基化改变，我们对结直肠癌（n = 835）、胃癌（n = 170）、肾癌（n = 143）、肺癌（n = 332）、前列腺癌（n = 869）、尿路上皮癌（n = 428）以及成熟B细胞淋巴瘤（n = 438）进行了匹配的病例对照研究。采用发现（对照）-验证（病例）策略，通过线性混合效应模型来识别与年龄、性别以及年龄与性别的交互作用相关的甲基化标记。使用来自苏格兰世代研究（GS）的汇总统计数据进一步检验验证情况。分别使用条件逻辑回归和Cox模型（风险比（HR））评估验证后的标记与癌症风险及生存之间的关联。我们分别发现了32,659个、23,141个和48个与年龄、性别以及年龄与性别的交互作用具有验证关联的CpG。使用GS汇总数据对这些CpG的验证率分别为94%、86%和91%。在一些与年龄相关的个别CpG处发现了与癌症风险和生存的显著关联。与之前使用表观遗传时钟的研究结果相反，表观遗传漂变与结直肠癌风险之间存在强烈的负向趋势。两个与 和 基因重叠的CpG处的甲基化分别与总体癌症（HR = 0.91，P = 7.7×10）和结直肠癌（HR = 1.52，P = 1.8×10）的生存相关，且具有显著的年龄与性别的交互作用。我们的结果可能为癌症早期检测和预后预测提供标记。
