Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study
- 1 March 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Epidemiology, Biomarkers & Prevention
- Vol. 30 (5), 953-964
- https://doi.org/10.1158/1055-9965.epi-20-1218
Abstract
Background: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. Methods: Genome-wide association study summary data were used to identify genetic variants associated with lifetime amount of smoking (n=126 variants) and ever having smoked regularly (n=112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). Results: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [odds ratio [OR] per 1-standard deviation (SD) increment: 1.13 (95% confidence interval [CI]: 1.00-1.26); P: 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer [OR per 1-SD increment: 1.21 (95% CI: 1.04-1.40); P: 0.01], colon cancer [OR: 1.31 (95% CI: 1.11-1.55); P: <0.01], and rectal cancer [OR: 1.36 (95% CI: 1.07-1.73); P: 0.01]. Ever having smoked regularly was not associated with risks of breast [OR: 1.01 (95% CI: 0.90-1.14); P: 0.85] or colorectal cancer [OR: 0.97 (95% CI: 0.86-1.10); P: 0.68]. Conclusions: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. Impact: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.Keywords
Funding Information
- National Cancer Institute
- National Institutes of Health
- U.S. Department of Health and Human Services (U01 CA137088, R01 CA059045, R01CA201407)
- NCI (t P30 CA015704)
- Clinical Research Program (PHRC-BRD09/C)
- U.S. Public Health Service (HHSN261201500005C)
- National Cancer Institute (U01 CA86308)
- Early Detection Research Network (P30 CA006973)
- National Institute on Aging (U01 AG18033)
- Cancer Research UK (18281/A29019)
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