Colorectal cancer incidence rates vary geographically and have changed over time. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, has doubled in many countries. The reasons for this increase are unknown. Here, we investigate whether mutational processes contribute to geographic and age-related differences by examining 981 colorectal cancer genomes from 11 countries. No major differences were found in microsatellite unstable cancers, but variations in mutation burden and signatures were observed in the 802 microsatellite-stable cases. Multiple signatures, most with unknown etiologies, exhibited varying prevalence in Argentina, Brazil, Colombia, Russia, and Thailand, indicating geographically diverse levels of mutagenic exposure. Signatures SBS88 and ID18, caused by the bacteria-produced mutagen colibactin, had higher mutation loads in countries with higher colorectal cancer incidence rates. SBS88 and ID18 were also enriched in early-onset colorectal cancers, being 3.3 times more common in individuals diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 responsible for about 25% of APC driver indels in colibactin-positive cases. This study reveals geographic and age-related variations in colorectal cancer mutational processes, and suggests that early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

Biomedical Sciences Graduate Program University of California San Diego La Jolla CA USA

Cancer Ageing and Somatic Mutation Wellcome Sanger Institute Cambridge UK

Centre for Biodiversity Genomics University of Guelph Guelph ON Canada

Clinic for Digestive Surgery 1st Surgical Clinic University Clinical Centre of Serbia Belgrade Serbia

Clinical Center ISCARE Prague Czech Republic

Clinical Epidemiology N N Blokhin National Medical Research Centre of Oncology Moscow Russia

Colon Cancer Reference Center A C Camargo Cancer Center Sao Paulo Brazil

Department of Bioengineering University of California San Diego La Jolla CA USA

Department of Biomedical Sciences and Biomedical Engineering Faculty of Medicine Prince of Songkla University Hat Yai Thailand

Department of Cellular and Molecular Medicine University of California San Diego La Jolla CA USA

Department of Colorectal Oncology Surgery Barretos Cancer Hospital Barretos Brazil

Department of Endoscopy Barretos Cancer Hospital Barretos Brazil

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine Łódź Poland

Department of Epidemiology A C Camargo Cancer Center Sao Paulo Brazil

Department of Genetics Universidade Federal do Rio Grande do Sul Porto Alegre Brazil

Department of Health Informatics Graduate School of Informatics Middle East Technical University Ankara Turkey

Department of Internal Medicine Faculty of Medicine Chiang Mai University Chiang Mai Thailand

Department of Oncology 2 Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology Anatomic Pathology Hospital de Clínicas de Porto Alegre Porto Alegre Rio Grande do Sul Brazil

Department of Pathology Barretos Cancer Hospital Barretos Brazil

Department of Pathology The Maria Sklodowska Cure National Research Institute of Oncology Warsaw Poland

Department of Pathology University Clinical Centre of Serbia Belgrade Serbia

Department of Surgery Division of Colorectal Surgery Hospital de Clínicas de Porto Alegre Porto Alegre Rio Grande do Sul Brazil

Department of Surgery Faculty of Medicine Prince of Songkla University Hat Yai Thailand

Digestive Oncology Research Center Digestive Disease Research Institute Tehran University of Medical Sciences Tehran Iran

Digital Genomics Group Structural Biology Program Spanish National Cancer Research Center Madrid Spain

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Division of Cancer Genomics National Cancer Center Research Institute Chuo ku Japan

Evidence Synthesis and Classification Branch International Agency for Research on Cancer Lyon France

Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France

Golestan Research Center of Gastroenterology and Hepatology Golestan University of Medical Sciences Gorgan Iran

Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic

Institute of Public Health and Preventive Medicine 2 Faculty of Medicine Charles University Prague Czech Republic

Instituto de Medicina Traslacional e Ingeniería Biomédica Buenos Aires Argentina

International Organization for Cancer Prevention and Research Belgrade Serbia

Laboratory of Molecular Medicine The Institute of Medical Science The University of Tokyo Minato ku Japan

Life and Health Sciences Research Institute School of Medicine Minho University Braga Portugal

Lunenfeld Tanenbaum Research Institute Sinai Health System Toronto ON Canada

Medical Genetics Service Hospital de Clínicas de Porto Alegre Porto Alegre Rio Grande do Sul Brazil

Molecular Oncology Research Center Barretos Cancer Hospital Barretos Brazil

Moores Cancer Center University of California San Diego La Jolla CA USA

National Cancer Institute Bangkok Thailand

Oncological pathology group Terry Fox National Tumor Bank National Cancer Institute Bogotá Colombia

Ontario Tumour Bank Ontario Institute for Cancer Research Toronto ON Canada

Parasites and Microbes Wellcome Sanger Institute Cambridge UK

Sanford Stem Cell Institute University of California San Diego La Jolla CA USA

Surgery Department 2 Faculty of Medicine Charles University and Central Military Hospital Prague Czech Republic

The Maria Sklodowska Cure National Research Institute of Oncology Warsaw Poland

Translational Medicine Research Center Faculty of Medicine Prince of Songkla University Hat Yai Thailand

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