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

doi:10.1038/s41416-023-02397-6

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Number of pages	8
Journal	British Journal of Cancer
Early online date	22 Aug 2023
DOIs	https://doi.org/10.1038/s41416-023-02397-6
Publication status	E-pub ahead of print - 22 Aug 2023

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Dissecting the pathogenic_ZHOU_DOA07082023_VOR_CC-BYFinal published version, 986 KBLicence: Creative Commons: Attribution (CC-BY)

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Colorectal cancer reduction through risk stratification of screening, follow-up and treatment
Theodoratou, E.
UK-based charities
1/05/17 → 30/04/23
Project: Research
Dissecting the Genetics of Colorectal Cancer: New Quinque
Dunlop, M.
UK-based charities
1/01/11 → 31/12/15
Project: Research

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Zhou, X., Xiao, Q., Jiang, F., Sun, J., Wang, L., Yu, L., Zhou, Y., Zhao, J., Zhang, H., Yuan, S., Timofeeva, M., Spiliopoulou, A., Mesa-Eguiagaray, I., Farrington, S. M., Law, P. J., Houlston, R. S., Ding, K., Dunlop, M. G., Theodoratou, E., & Li, X. (2023). Dissecting the pathogenic effects of smoking and its hallmarks in blood DNA methylation on colorectal cancer risk. British Journal of Cancer. Advance online publication. https://doi.org/10.1038/s41416-023-02397-6

@article{0fecba183c594b8e8e448237f8263d46,

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

abstract = "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.",

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

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: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = aug,

day = "22",

doi = "10.1038/s41416-023-02397-6",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

publisher = "Nature Publishing Group",

}

Zhou, X, Xiao, Q, Jiang, F, Sun, J, Wang, L, Yu, L, Zhou, Y, Zhao, J, Zhang, H, Yuan, S, Timofeeva, M, Spiliopoulou, A, Mesa-Eguiagaray, I, Farrington, SM, Law, PJ, Houlston, RS, Ding, K, Dunlop, MG , Theodoratou, E & Li, X 2023, 'Dissecting the pathogenic effects of smoking and its hallmarks in blood DNA methylation on colorectal cancer risk', British Journal of Cancer. https://doi.org/10.1038/s41416-023-02397-6

TY - JOUR

T1 - Dissecting the pathogenic effects of smoking and its hallmarks in blood DNA methylation on colorectal cancer risk

AU - Zhou, Xuan

AU - Xiao, Qian

AU - Jiang, Fangyuan

AU - Sun, Jing

AU - Wang, Lijuan

AU - Yu, Lili

AU - Zhou, Yajing

AU - Zhao, Jianhui

AU - Zhang, Han

AU - Yuan, Shuai

AU - Timofeeva, Maria

AU - Spiliopoulou, Athina

AU - Mesa-Eguiagaray, Ines

AU - Farrington, Susan M

AU - Law, Philip J

AU - Houlston, Richard S

AU - Ding, Kefeng

AU - Dunlop, Malcolm G

AU - Theodoratou, Evropi

AU - Li, Xue

N1 - 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).

PY - 2023/8/22

Y1 - 2023/8/22

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-023-02397-6

DO - 10.1038/s41416-023-02397-6

M3 - Article

C2 - 37608097

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

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

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Projects

Colorectal cancer reduction through risk stratification of screening, follow-up and treatment

Dissecting the Genetics of Colorectal Cancer: New Quinque

Cite this