BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide potential prevention treatments.

Behavioral and Epidemiology Research Group American Cancer Society Atlanta Georgia

Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia

Biomedical Informatics Program Dept of Biomedical Data Sciences Stanford University Stanford California

Broad Institute of MIT and Harvard Cambridge Massachusetts

Cancer Epidemiology Division Cancer Council Victoria Melbourne Victoria Australia

Center for Gastrointestinal Biology and Disease University of North Carolina Chapel Hill North Carolina

Center for Public Health Genomics Department of Public Health Sciences University of Virginia Charlottesville Virginia

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Victoria Australia

Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston Massachusetts

Colorectal Cancer Group ONCOBELL Program Bellvitge Biomedical Research Institute L'Hospitalet de Llobregat Barcelona Spain

Consortium for Biomedical Research in Epidemiology and Public Health Madrid Spain

Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom

Department of Epidemiology Harvard T H Chan School of Public Health Boston Massachusetts

Department of Epidemiology Johns Hopkins Bloomberg School of Public Health Baltimore Maryland

Department of Epidemiology Richard M Fairbanks School of Public Health Indianapolis Indiana

Department of Family Medicine University of Virginia Charlottesville Virginia

Department of General Surgery University of Virginia School of Medicine Charlottesville Virginia

Department of Genetics and Genome Sciences Case Western Reserve University Cleveland Ohio

Department of Genetics Department of Computer Science Stanford University Stanford California

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Internal Medicine University of Utah Salt Lake City Utah

Department of Laboratory Medicine and Pathology Mayo Clinic Arizona Scottsdale Arizona

Department of Medical Oncology and Therapeutics Research City of Hope National Medical Center Duarte California

Department of Medicine and Epidemiology University of Pittsburgh Medical Center Pittsburgh Pennsylvania

Department of Medicine Samuel Oschin Comprehensive Cancer Institute Cedars Sinai Medical Center Los Angeles California

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague and Biomedical Center Medical Faculty Pilsen Czech Republic

Department of Nutritional Sciences University of Michigan School of Public Health Ann Arbor Michigan

Department of Oncologic Pathology Dana Farber Cancer Institute Boston Massachusetts

Department of Pathology School of Medicine Umm Al Qura'a University Saudi Arabia

Department of Population Health Sciences University of Utah Salt Lake City Utah

Department of Public Health and Primary Care University of Cambridge Cambridge United Kingdom

Department of Radiation Sciences Oncology Unit Umeå University Umeå Sweden

Digestive Diseases and Microbiota Group Girona Biomedical Research Institute Salt Girona Spain

Division of Biostatistics Department of Population and Public Health Sciences Keck School of Medicine University of Southern California Los Angeles California

Division of Cancer Epidemiology and Genetics NCI NIH Bethesda Maryland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg Germany

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston Massachusetts

Division of Human Nutrition and Health Wageningen University and Research Wageningen the Netherlands

Division of Preventive Oncology German Cancer Research Center Heidelberg Germany

Division of Research Kaiser Permanente Northern California Oakland California

Genomic Medicine Institute Cleveland Clinic Cleveland Ohio

German Cancer Consortium Heidelberg Germany

Huntsman Cancer Institute Salt Lake City Utah

Institute of Cancer Research Department of Medicine 1 Medical University Vienna Vienna Austria

Institute of Environmental Medicine Karolinska Institutet Stockholm Sweden

Leeds Institute of Cancer and Pathology University of Leeds Leeds United Kingdom

Lunenfeld Tanenbaum Research Institute Mount Sinai Hospital University of Toronto Toronto Ontario Canada

Memorial University of Newfoundland Discipline of Genetics St John's Canada

Nutrition and Metabolism Branch International Agency for Research on Cancer Lyon France

Oncology Data Analytics Program Catalan Institute of Oncology L'Hospitalet de Llobregat Barcelona Spain

Population and Cancer Prevention Program Case Comprehensive Cancer Center Cleveland Ohio

Program in MPE Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston Massachusetts

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle Washington

School of Public Health Capital Medical University Beijing P R China

School of Public Health University of Washington Seattle Washington

Service de Génétique Médicale Centre Hospitalier Universitaire Nantes Nantes France

Slone Epidemiology Center at Boston University Boston Massachusetts

SWOG Statistical Center Fred Hutchinson Cancer Research Center Seattle Washington

University of Hawaii Cancer Center Honolulu Hawaii

Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

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