Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2021-05, Vol.30 (5), p.953-964
• Main Authors: Dimou, Niki, Yarmolinsky, James, Bouras, Emmanouil, Tsilidis, Konstantinos K, Martin, Richard M, Lewis, Sarah J, Gram, Inger T, Bakker, Marije F, Brenner, Hermann, Figueiredo, Jane C, Fortner, Renée T, Gruber, Stephen B, van Guelpen, Bethany, Hsu, Li, Kaaks, Rudolf, Kweon, Sun-Seog, Lin, Yi, Lindor, Noralane M, Newcomb, Polly A, Sánchez, Maria-Jose, Severi, Gianluca, Tindle, Hilary A, Tumino, Rosario, Weiderpass, Elisabete, Gunter, Marc J, Murphy, Neil
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - epidemiology; Causality; Colorectal Neoplasms - epidemiology; Female; Genome-Wide Association Study; Humans; Life Sciences; Male; Mendelian Randomization Analysis - methods; Risk Factors; Santé publique et épidémiologie; Smoking - epidemiology
• ISSN: 1055-9965; 1538-7755; 1538-7755
• DOI: 10.1158/1055-9965.EPI-20-1218

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. Genome-Wide Association Study summary data were used to identify genetic variants associated with lifetime amount of smoking ( = 126 variants) and ever having smoked regularly ( = 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). In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [OR per 1-SD increment: 1.13; 95% confidence interval (CI): 1.00-1.26; = 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; = 0.01), colon cancer (OR, 1.31; 95% CI, 1.11-1.55; < 0.01), and rectal cancer (OR, 1.36; 95% CI, 1.07-1.73; = 0.01). Ever having smoked regularly was not associated with risks of breast (OR, 1.01; 95% CI, 0.90-1.14; = 0.85) or colorectal cancer (OR, 0.97; 95% CI, 0.86-1.10; = 0.68). 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. The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.