Geographic and age variations in mutational processes in colorectal cancer

Marcos Díaz-Gay, Wellington Santos, Sarah Moody, Mariya Kazachkova, Ammal Abbasi, Christopher D. Steele, Raviteja Vangara, Sergey Senkin, Jingwei Wang, Stephen Fitzgerald, Erik N. Bergstrom, Azhar Khandekar, Burçak Otlu, Behnoush Abedi-Ardekani, Ana Carolina Carvalho, Thomas Cattiaux, Ricardo Cortez Cardoso Penha, Valérie Gaborieau, Priscilia Chopard, Christine Carreira, Saamin Cheema, Calli Latimer, Jon W. Teague, Anush Mukeriya, David Zaridze, Riley Cox, Monique Albert, Larry Phouthavongsy, Steven Gallinger, Reza Malekzadeh, Ahmadreza Niavarani, Marko Miladinov, Katarina Erić, Sasa Milosavljevic, Suleeporn Sangrajrang, Maria Paula Curado, Samuel Aguiar, Rui Manuel Reis, Monise Tadin Reis, Luis Gustavo Romagnolo, Denise Peixoto Guimarães, Ivana Holcatova, Jaroslav Kalvach, Carlos Alberto Vaccaro, Tamara Alejandra Piñero, Beata Świątkowska, Jolanta Lissowska, Katarzyna Roszkowska-Purska, Antonio Huertas-Salgado, Tatsuhiro Shibata, Satoshi Shiba, Surasak Sangkhathat, Taned Chitapanarux, Gholamreza Roshandel, Patricia Ashton-Prolla, Daniel C. Damin, Francine Hehn Oliveira, Laura Humphreys, Trevor D. Lawley, Sandra Perdomo, Michael R. Stratton, Paul Brennan and Ludmil B. Alexandrov ()
Additional contact information
Marcos Díaz-Gay: University of California San Diego
Wellington Santos: International Agency for Research on Cancer (IARC/WHO)
Sarah Moody: Wellcome Sanger Institute
Mariya Kazachkova: University of California San Diego
Ammal Abbasi: University of California San Diego
Christopher D. Steele: University of California San Diego
Raviteja Vangara: University of California San Diego
Sergey Senkin: International Agency for Research on Cancer (IARC/WHO)
Jingwei Wang: Wellcome Sanger Institute
Stephen Fitzgerald: Wellcome Sanger Institute
Erik N. Bergstrom: University of California San Diego
Azhar Khandekar: University of California San Diego
Burçak Otlu: University of California San Diego
Behnoush Abedi-Ardekani: International Agency for Research on Cancer (IARC/WHO)
Ana Carolina Carvalho: International Agency for Research on Cancer (IARC/WHO)
Thomas Cattiaux: International Agency for Research on Cancer (IARC/WHO)
Ricardo Cortez Cardoso Penha: International Agency for Research on Cancer (IARC/WHO)
Valérie Gaborieau: International Agency for Research on Cancer (IARC/WHO)
Priscilia Chopard: International Agency for Research on Cancer (IARC/WHO)
Christine Carreira: International Agency for Research on Cancer (IARC/WHO)
Saamin Cheema: Wellcome Sanger Institute
Calli Latimer: Wellcome Sanger Institute
Jon W. Teague: Wellcome Sanger Institute
Anush Mukeriya: N. N. Blokhin National Medical Research Centre of Oncology
David Zaridze: N. N. Blokhin National Medical Research Centre of Oncology
Riley Cox: Ontario Institute for Cancer Research
Monique Albert: Ontario Institute for Cancer Research
Larry Phouthavongsy: Ontario Institute for Cancer Research
Steven Gallinger: Sinai Health System
Reza Malekzadeh: Tehran University of Medical Sciences
Ahmadreza Niavarani: Tehran University of Medical Sciences
Marko Miladinov: University Clinical Centre of Serbia
Katarina Erić: University Clinical Centre of Serbia
Sasa Milosavljevic: International Organization for Cancer Prevention and Research
Suleeporn Sangrajrang: National Cancer Institute
Maria Paula Curado: A. C. Camargo Cancer Center
Samuel Aguiar: A. C. Camargo Cancer Center
Rui Manuel Reis: Barretos Cancer Hospital
Monise Tadin Reis: Barretos Cancer Hospital
Luis Gustavo Romagnolo: Barretos Cancer Hospital
Denise Peixoto Guimarães: Barretos Cancer Hospital
Ivana Holcatova: Charles University and University Hospital Motol
Jaroslav Kalvach: Charles University and Central Military Hospital
Carlos Alberto Vaccaro: Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB)–CONICET–Universidad Hospital Italiano de Buenos Aires (UHIBA) y Hospital Italiano de Buenos Aires (HIBA)
Tamara Alejandra Piñero: Instituto de Medicina Traslacional e Ingeniería Biomédica (IMTIB)–CONICET–Universidad Hospital Italiano de Buenos Aires (UHIBA) y Hospital Italiano de Buenos Aires (HIBA)
Beata Świątkowska: Nofer Institute of Occupational Medicine
Jolanta Lissowska: The Maria Sklodowska-Cure National Research Institute of Oncology
Katarzyna Roszkowska-Purska: The Maria Sklodowska-Cure National Research Institute of Oncology
Antonio Huertas-Salgado: National Cancer Institute
Tatsuhiro Shibata: The University of Tokyo
Satoshi Shiba: National Cancer Center Research Institute
Surasak Sangkhathat: Prince of Songkla University
Taned Chitapanarux: Chiang Mai University
Gholamreza Roshandel: Golestan University of Medical Sciences
Patricia Ashton-Prolla: Universidade Federal do Rio Grande do Sul (UFRGS)
Daniel C. Damin: Hospital de Clínicas de Porto Alegre (HCPA)
Francine Hehn Oliveira: Hospital de Clínicas de Porto Alegre (HCPA)
Laura Humphreys: Wellcome Sanger Institute
Trevor D. Lawley: Wellcome Sanger Institute
Sandra Perdomo: International Agency for Research on Cancer (IARC/WHO)
Michael R. Stratton: Wellcome Sanger Institute
Paul Brennan: International Agency for Research on Cancer (IARC/WHO)
Ludmil B. Alexandrov: University of California San Diego

Nature, 2025, vol. 643, issue 8070, 230-240

Abstract: Abstract Incidence rates of colorectal cancer vary geographically and have changed over time1. 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 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 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 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 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.

Date: 2025
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DOI: 10.1038/s41586-025-09025-8

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