Causal Effects of Lifetime Smoking on Breast and Colorectal Cancer Risk: Mendelian Randomization Study.
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France. DimouN@fellows.iarc.fr.
- Department of Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
- Laboratory of Hygiene, Social & Preventive Medicine and Medical Statistics, Department of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- Department of Community Medicine, Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway.
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, University Utrecht, Utrecht, the Netherlands.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Center for Precision Medicine, City of Hope National Medical Center, Duarte, California.
- Department of Radiation Sciences, Oncology Unit, Umea University, Umea, Sweden.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea.
- Department of Health Science Research, Mayo Clinic, Scottsdale, Arizona.
- Escuela Andaluza de Salud Pública (EASP), Granada, Spain.
- CESP UMR1018, Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, Villejuif, France.
- General Internal Medicine, Vanderbilt University Medical Center, Vanderbilt University, Nashville, Tennessee.
- Cancer Registry and Histopathology Department, Provincial Health Authority (ASP 7) Ragusa, Ragusa, Italy.
- Office of the Director, International Agency for Research on Cancer, World Health Organization, Lyon, France.
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
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 [OR per 1-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.
- 2014-0244: Colorectal Tumor Risk Prediction in the PLCO Trial (ULRIKE PETERS)