Dissecting the pathogenic effects of smoking and its hallmarks in blood DNA methylation on colorectal cancer risk

Xuan Zhou, Qian Xiao, Fangyuan Jiang, Jing Sun, Lijuan Wang, Lili Yu, Yajing Zhou, Jianhui Zhao, Han Zhang, Shuai Yuan, Maria Timofeeva, Athina Spiliopoulou, Ines Mesa-Eguiagaray, Susan M. Farrington, Philip J. Law, Richard S. Houlston, Kefeng Ding, Malcolm G. Dunlop, Evropi Theodoratou, Xue Li*


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Background: Tobacco smoking is suggested as a risk factor for colorectal cancer (CRC), but the complex relationship and the potential pathway are not fully understood. Methods: We performed two-sample Mendelian randomisation (MR) analyses with genetic instruments for smoking behaviours and related DNA methylation in blood and summary-level GWAS data of colorectal cancer to disentangle the relationship. Colocalization analyses and prospective gene-environment interaction analyses were also conducted as replication. Results: Convincing evidence was identified for the pathogenic effect of smoking initiation on CRC risk and suggestive evidence was observed for the protective effect of smoking cessation in the univariable MR analyses. Multivariable MR analysis revealed that these associations were independent of other smoking phenotypes and alcohol drinking. Genetically predicted methylation at CpG site cg17823346 [ZMIZ1] were identified to decrease CRC risk; while genetically predicted methylation at cg02149899 would increase CRC risk. Colocalization and gene-environment interaction analyses added further evidence to the relationship between epigenetic modification at cg17823346 [ZMIZ1] as well as cg02149899 and CRC risk. Discussion: Our study confirms the significant association between tobacco smoking, DNA methylation and CRC risk and yields a novel insight into the pathogenic effect of tobacco smoking on CRC risk.

TidsskriftBritish Journal of Cancer
Udgave nummer8
Sider (fra-til)1306-1313
StatusUdgivet - okt. 2023

Bibliografisk note

Funding Information:
XL is supported by the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (LR22H260001) and the National Nature Science Foundation of China (No. 82204019). ET is supported by a CRUK Career Development Fellowship (C31250/A22804). AS acknowledges support from the Academy of Medical Sciences/the Wellcome Trust/the Government Department of Business, Energy and Industrial Strategy/the British Heart Foundation/Diabetes UK Springboard Award [SBF006\1109]. The work is supported by Programme Grant funding from Cancer Research UK (C348/A12076) and by funding for the infrastructure and staffing of the Edinburgh CRUK Cancer Research Centre. This work is also funded by a grant to MGD as Project Leader with the MRC Human Genetics Unit Centre Grant (U127527198). This work is also supported by the Natural Science Foundation of Zhejiang Province (LBY20H160002) to QX and the project of the regional diagnosis and treatment center of the Health Planning Committee (No. JBZX-201903) to KD.

Publisher Copyright:
© 2023, The Author(s).


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