Exploring the cross-cancer effect of smoking and its fingerprints in blood DNA methylation on multiple cancers: A Mendelian randomization study

Yajing Zhou, Xuan Zhou, Jing Sun, Lijuan Wang, Jianhui Zhao, Jie Chen, Shuai Yuan, Yazhou He, Maria Timofeeva, Athina Spiliopoulou, Ines Mesa-Eguiagaray, Susan M. Farrington, Kefeng Ding, Malcolm G. Dunlop, Xiao Qian*, Evropi Theodoratou*, Xue Li*


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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.

TidsskriftInternational Journal of Cancer
Udgave nummer8
Sider (fra-til)1477-1486
StatusUdgivet - 15. okt. 2023

Bibliografisk note

Funding Information:
Xue Li is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (82204019). Yazhou He is supported by the NSFC (82103918) and Sichuan Provincial Nature Science Foundation (2022NSFSC1314). Evropi Theodoratou is supported by a CRUK Career Development Fellowship (C31250/A22804). Kefeng Ding is supported by the project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX‐201903). This work is also funded by a grant to Malcolm G Dunlop as Project Leader with the MRC Human Genetics Unit Centre Grant (U127527198).

Funding Information:
The authors thank the Heart and Aging Research in the Genetic Epidemiology Consortium, GoDMC, ECAC, E2C2 and UK Biobank, PRACTICAL Consortium, BCAC, OCAC, ILCCO, Finngen Consortium and the GERA database. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH and NINDS.

Publisher Copyright:
© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.


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