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We conducted two\u2010sample Mendelian randomization (MR) analyses respectively on smoking behaviors (age of smoking initiation, smoking initiation, smoking cessation, and lifetime smoking index [LSI]) and smoking\u2010related DNA methylation to investigate their effect on 15 site\u2010specific cancers, based on a genome\u2010wide association study (GWAS) of 1.2 million European individuals and an epigenome\u2010WAS (EWAS) of 5907 blood samples of Europeans for smoking and 15 GWASs of European ancestry for multiple site\u2010specific cancers. Significantly identified CpG sites were further used for colocalization analysis, and those with cross\u2010cancer effect were validated by overlapping with tissue\u2010specific 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\u2010specific 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\u2010cancer effect, among which cg06639488 (EFNA1), cg12101586 (CYP1A1) and cg14142171 (HLA\u2010L) 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\u20101.00), 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\u2010involved cross\u2010cancer pathways.<\/jats:p>","DOI":"10.1002\/ijc.34656","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T10:25:18Z","timestamp":1689330318000},"page":"1477-1486","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Exploring the cross\u2010cancer effect of smoking and its fingerprints in blood <scp>DNA<\/scp> methylation on multiple cancers: A Mendelian randomization study"],"prefix":"10.1002","volume":"153","author":[{"given":"Yajing","family":"Zhou","sequence":"first","affiliation":[{"name":"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"},{"name":"Department of Big Data in Health Science, School of Public Health and The Second 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Zhejiang University School of Medicine  Hangzhou China"},{"name":"Centre for Global Health Sciences, Usher Institute University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhui","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Big Data in Health Science, School of Public Health and The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuai","family":"Yuan","sequence":"additional","affiliation":[{"name":"Unit of Cardiovascular and Nutritional Epidemiology Institute of Environmental Medicine, Karolinska Institutet  Stockholm 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