BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. CRC has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization (MR) analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC. PATIENTS AND METHODS: We conducted a GWAS meta-analysis of 6176 EOCRC cases and 65 829 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT), the Colon Cancer Family Registry (CCFR), and the UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample MR. RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, which were not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (odds ratio 1.80, 95% confidence interval 1.47-2.22) but show that most of the common genetic susceptibility was from noncoding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC-susceptibility genes, and in addition to pathways such as transforming growth factor (TGF) β, suppressor of Mothers Against Decapentaplegic (SMAD), bone morphogenetic protein (BMP) and phosphatidylinositol kinase (PI3K) signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors-such as body fat percentage, waist circumference, waist-to-hip ratio, basal metabolic rate, and fasting insulin-higher alcohol drinking, and lower education attainment with increased EOCRC risk. CONCLUSIONS: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk-stratify individuals for personalized screening strategies or other interventions.

Cancer Prevention and Control Program Catalan Institute of Oncology IDIBELL L'Hospitalet de Llobregat Barcelona; CIBER de Epidemiología y Salud Pública Madrid; Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Center for Cancer Research Medical University of Vienna Vienna Austria

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

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

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health The University of Melbourne Melbourne Australia; Cancer Epidemiology Division Cancer Council Victoria Melbourne; Physical Activity Laboratory Baker Heart and Diabetes Institute Melbourne Australia

Colorectal Oncogenomics Group Department of Clinical Pathology The University of Melbourne Parkville; University of Melbourne Centre for Cancer Research Victorian Comprehensive Cancer Centre Melbourne; Genomic Medicine and Family Cancer Clinic Royal Melbourne Hospital Parkville Australia

Department of Colorectal Surgery North Bristol NHS Trust Bristol UK

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK; Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece

Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx USA

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston; Department of Medical Oncology Dana Farber Cancer Institute Boston; Program in Molecular Pathological Epidemiology Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston; Department of Oncologic Pathology Dana Farber Cancer Institute Boston

Department of Epidemiology Harvard T H Chan School of Public Health Harvard University Boston; Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston USA; Department of Nutrition Harvard T H Chan School of Public Health Boston USA

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

Department of Molecular Biology of Cancer Institute of Experimental Medicine of the Czech Academy of Sciences Prague; Institute of Biology and Medical Genetics 1st Faculty of Medicine Charles University Prague; Faculty of Medicine and Biomedical Center in Pilsen Charles University Pilsen Czech Republic

Department of Nutrition Harvard T H Chan School of Public Health Boston USA

Department of Radiation Sciences Oncology Unit Umeå University Umeå; Wallenberg Centre for Molecular Medicine Umeå University Umeå Sweden

Division of Cancer Epidemiology and Genetics National Cancer Institute National Institutes of Health Bethesda USA

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

Division of Epidemiology Department of Population Health New York University School of Medicine New York

Division of Gastroenterology Massachusetts General Hospital and Harvard Medical School Boston; Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston; Clinical and Translational Epidemiology Unit Massachusetts General Hospital and Harvard Medical School Boston USA

Division of Human Genetics Department of Internal Medicine The Ohio State University Comprehensive Cancer Center Columbus

Division of Public Health Sciences Department of Surgery Washington University School of Medicine St Louis; Division of Gastroenterology Department of Medicine Washington University School of Medicine St Louis; Alvin J Siteman Cancer Center St Louis

Epigenomics and Mechanisms Branch International Agency for Research on Cancer World Health Organization Lyon France; Cancer Research UK Cambridge Institute University of Cambridge Cambridge UK

Leeds Institute of Cancer and Pathology University of Leeds Leeds UK

Medical Research Council Bristol Biomedical Research Centre University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol Bristol

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

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

Nutrition and Metabolism Branch International Agency for Research on Cancer World Health Organization Lyon France; Department of Epidemiology and Biostatistics School of Public Health Imperial College London London UK

Nutrition and Metabolism Branch International Agency for Research on Cancer World Health Organization Lyon France; Early Cancer Institute Department of Oncology School of Clinical Medicine University of Cambridge Cambridge UK

Ontario Health Toronto; Dalla Lana School of Public Health University of Toronto Toronto Canada

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle

Public Health Sciences Division Fred Hutchinson Cancer Research Center Seattle; Department of Epidemiology University of Washington Seattle USA

University of Hawaii Cancer Center Honolulu USA

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