Geographic and age variations in mutational processes in colorectal cancer
Status Publisher Language English Country England, Great Britain Media print-electronic
Document type Journal Article
PubMed
40267983
DOI
10.1038/s41586-025-09025-8
PII: 10.1038/s41586-025-09025-8
Knihovny.cz E-resources
- Publication type
- Journal Article MeSH
Colorectal cancer incidence rates vary geographically and have changed over time1. 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 countries2-5. 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 colibactin6,7, 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.
2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic
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
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 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 Internal Medicine Faculty of Medicine Chiang Mai University Chiang Mai Thailand
Department of Pathology Barretos Cancer Hospital Barretos Brazil
Department of Pathology University Clinical Centre of Serbia Belgrade Serbia
Department of Surgery Faculty of Medicine Prince of Songkla University Hat Yai Thailand
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
Genomic Epidemiology Branch International Agency for Research on Cancer Lyon France
Institute of Animal Physiology and Genetics Czech Academy of Science Libechov Czech Republic
Instituto de Medicina Traslacional e Ingeniería Biomédica Buenos Aires Argentina
International Organization for Cancer Prevention and Research Belgrade Serbia
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
The Maria Sklodowska Cure National Research Institute of Oncology Warsaw Poland
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