Geographic and age variations in mutational processes in colorectal cancer

Incidence rates of colorectal cancer vary geographically and have changed over time<sup>1</sup>. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries<sup>2-5</sup>. 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 aetiologies, 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<sup>6,7</sup>, 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 who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being 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 mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

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Journal
Nature
Published
2025-04-23
DOI
https://doi.org/10.1038/s41586-025-09025-8
Citations
76
Primary Topic
Genetic factors in colorectal cancer
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article
Field-Weighted Citation Impact
111.84
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article

Geographic and age variations in mutational processes in colorectal cancer

Beata Świątkowska, Jolanta Lissowska, Paul Brennan, Давид Заридзе et al.
76 citations
Nature
Genetic factors in colorectal cancer
111.84
article

Geographic and age variations in mutational processes in colorectal cancer

Beata Świątkowska, Jolanta Lissowska, Paul Brennan, Давид Заридзе, Satoshi Shiba, S. Senkin, Reza Malekzadeh, Steven Gallinger, Saamin Cheema, Samuel Aguiar, Laura Humphreys, Jaroslav Kalvach, Marko Miladinov, Ahmadreza Niavarani, Ivana Holcátová, Daniel C. Damin, Larry Phouthavongsy, Erik N. Bergstrom, Rui Manuel Reis, Katarina Erić, Francine Hehn de Oliveira, Burçak Otlu, Sandra Pérdomo, Trevor D. Lawley, Wellington dos Santos, Denise Peixoto Guimarães, Priscilia Chopard, Ammal Abbasi, Gholamreza Roshandel, Taned Chitapanarux, Katarzyna Roszkowska‐Purska, Tamara Alejandra Piñero, Tatsuhiro Shibata, Suleeporn Sangrajrang, Valérie Gaborieau, Christopher D. Steele, Michael R. Stratton, Behnoush Abedi‐Ardekani, Surasak Sangkhathat, Anush Mukeriya, Ana Carolina de Carvalho, Azhar Khandekar, Ricardo Cortez Cardoso Penha, Saša Milosavljević, Monique Albert, Ludmil B. Alexandrov, Raviteja Vangara, Patrícia Ashton‐Prolla, Marcos Díaz‐Gay, Luís Gustavo Capochin Romagnolo, Carlos Vaccaro, Mariya Kazachkova, Calli Latimer, María Paula Curado, Monise Tadin Reis, Thomas Cattiaux, Jingwei Wang, Sarah Moody, Stephen Fitzgerald, Antonio Huertas, Jon W. Teague, Riley Cox, Christine Carreira
article en
76 citations

Abstract

Incidence rates of colorectal cancer vary geographically and have changed over time<sup>1</sup>. Notably, in the past two decades, the incidence of early-onset colorectal cancer, which affects individuals below 50 years of age, has doubled in many countries<sup>2-5</sup>. 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 aetiologies, 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<sup>6,7</sup>, 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 who were diagnosed before 40 years of age than in those over 70 years of age, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 being 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 mutagenic exposure to colibactin-producing bacteria in early life may contribute to the increasing incidence of early-onset colorectal cancer.

NatureVol. 643(8070)
Ontario Institute for Cancer Research (CA), Universidade Federal do Rio Grande do Sul (BR), Prince of Songkla University (TH), Golestan University (IR), Middle East Technical University (TR), Nofer Institute of Occupational Medicine (PL), Lunenfeld-Tanenbaum Research Institute (CA), Charles University (CZ), UC San Diego Health System (US), Hospital Italiano de Buenos Aires (AR), Wellcome Sanger Institute (GB), AC Camargo Hospital (BR), University of California San Diego (US), Spanish National Cancer Research Centre (ES), Russian Cancer Research Center NN Blokhin (RU), Hospital de Câncer de Barretos (BR), Terry Fox Research Institute (CA), Hospital de Clínicas de Porto Alegre (BR), University Hospital in Motol (CZ), National Cancer Institute of Thailand (TH), Czech Academy of Sciences, Institute of Animal Physiology and Genetics (CZ), Central Military Hospital (NL), Iscare I.V.F (CZ), National Institute of Oncology (HU), Golestan University of Medical Sciences (IR), Sinai Health System (CA), Military University Hospital Prague (CZ), University Clinical Centre (PL), La Jolla Bioengineering Institute (US), National Cancer Institute (US), National Medical Research Center of Cardiology (RU), The Maria Sklodowska-Curie National Research Institute of Oncology (PL), Centre international de recherche sur le cancer (FR), Division of Cancer Epidemiology and Genetics, Chiang Mai University (TH), Tehran University of Medical Sciences (IR), The University of Tokyo (JP), University of Guelph (CA), University of Minho (PT)
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Genetic factors in colorectal cancer
111.84
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