Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Int J Cancer. 2023 Oct 15;153(8):1477-1486. doi: 10.1002/ijc.34656. Epub 2023 Jul 14.
Aberrant smoking-related DNA methylation has been widely investigated as a carcinogenesis mechanism, but whether the cross-cancer epigenetic pathways exist remains unclear. We conducted two-sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking-related DNA methylation to investigate their effect on 15 site-specific cancers, based on a genome-wide association study (GWAS) of 1.2 million European individuals and an epigenome-WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site-specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross-cancer effect were validated by overlapping with tissue-specific eQTLs. In the genomic MR, smoking measurements of smoking initiation, smoking cessation and LSI were suggested to be casually associated with risk of seven types of site-specific cancers, among which cancers at lung, cervix and colorectum were provided with strong evidence. In the epigenetic MR, methylation at 75 CpG sites were reported to be significantly associated with increased risks of multiple cancers. Eight out of 75 CpG sites were observed with cross-cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA-L) were validated by eQTLs at specific cancer sites, and cg07932199 (ATXN2) had strong evidence to be associated with cancers of lung (coefficient, 0.65, 95% confidence interval [CI], 0.31-1.00), colorectum (0.90 [0.61, 1.18]), breast (0.31 [0.20, 0.43]) and endometrium (0.98 [0.68, 1.27]). These findings highlight the potential practices targeting DNA methylation-involved cross-cancer pathways.
吸烟相关的 DNA 甲基化异常已被广泛研究作为一种致癌机制，但跨癌种的表观遗传途径是否存在仍不清楚。我们分别对吸烟行为（吸烟起始年龄、开始吸烟、戒烟和终生吸烟指数[LSI]）和与吸烟相关的 DNA 甲基化进行了两样本 Mendelian 随机化（MR）分析，基于对 120 万欧洲个体的全基因组关联研究（GWAS）和对 5907 个欧洲人血液样本的吸烟相关的表观基因组-WAS（EWAS）以及 15 个欧洲祖先的多种特定部位癌症的 GWAS。显著鉴定的 CpG 位点进一步用于共定位分析，并且那些具有跨癌种效应的 CpG 位点通过与组织特异性 eQTL 重叠进行验证。在基因组 MR 中，吸烟起始、戒烟和 LSI 的吸烟测量值被认为与七种特定部位癌症的风险具有因果关系，其中肺癌、宫颈癌和结直肠癌提供了强有力的证据。在表观遗传 MR 中，报告了 75 个 CpG 位点的甲基化与多种癌症的风险增加显著相关。在这 75 个 CpG 位点中，有 8 个观察到具有跨癌种效应，其中 cg06639488（EFNA1）、cg12101586（CYP1A1）和 cg14142171（HLA-L）在特定癌症部位通过 eQTLs 得到验证，cg07932199（ATXN2）有强有力的证据表明与肺癌（系数，0.65，95%置信区间[CI]，0.31-1.00）、结直肠癌（0.90[0.61, 1.18]）、乳腺癌（0.31[0.20, 0.43]）和子宫内膜癌（0.98[0.68, 1.27]）相关。这些发现强调了针对 DNA 甲基化涉及的跨癌种途径的潜在实践。
