Journal Article

Geographic and age variations in mutational processes in colorectal cancer

Cheema, Saamin, Sangkhathat, Surasak, Abedi-Ardekani, Behnoush, Penha, Ricardo Cortez Cardoso, Curado, Maria Paula, Díaz-Gay, Marcos, Fitzgerald, Stephen, Vangara, Raviteja, Świątkowska, Beata, Reis, Rui Manuel, Huertas-Salgado, Antonio, Damin, Daniel C., Perdomo, Sandra, de Oliveira, Francine Hehn, Humphreys, Laura, Mukeriya, Anush, Teague, Jon W., Kazachkova, Mariya, Otlu, Burçak, Roshandel, Gholamreza, Ashton-Prolla, Patricia, Latimer, Calli, Niavarani, Ahmadreza, Chopard, Priscilia, Reis, Monise Tadin, Chitapanarux, Taned, Stratton, Michael R., Roszkowska-Purska, Katarzyna, Wang, Jingwei, Bergstrom, Erik N., Cattiaux, Thomas, Aguiar, Samuel, Miladinov, Marko, Milosavljevic, Sasa, Senkin, Sergey, Khandekar, Azhar, Shiba, Satoshi, Alexandrov, Ludmil B., Phouthavongsy, Larry, Lissowska, Jolanta, Gaborieau, Valérie, Albert, Monique, Gallinger, Steven, Cox, Riley, Erić, Katarina, Piñero, Tamara Alejandra, Holcatova, Ivana, Lawley, Trevor D., de Carvalho, Ana Carolina, Zaridze, David, Kalvach, Jaroslav, Sangrajrang, Suleeporn, Brennan, Paul, Abbasi, Ammal, Steele, Christopher D., Moody, Sarah, dos

2025

Overview

Incidence rates of colorectal cancer vary geographically and have changed over time 1 . 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 2 , 3 , 4 – 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 colibactin 6 , 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. Analysis of genomic data from 981 colorectal cancers from participants in 11 countries reveals variations in mutational signatures of microsatellite-stable cancers that are dependent on geographical origin and age at which the cancer was diagnosed.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 45/70 / 631/67/1504/1885 / 631/67/2324 / 631/67/69 / Adenomatous polyposis coli / Adult / Age / Age Factors / Age of Onset / Aged / Argentina - epidemiology / Bacteria / Brazil - epidemiology / Cancer / Chemotherapy / Colombia - epidemiology / Colorectal cancer / Colorectal Neoplasms - epidemiology / Colorectal Neoplasms - genetics / DNA repair / Epidemiology / Exposure / Female / Humanities and Social Sciences / Humans / Incidence / INDEL Mutation - genetics / Male / Microsatellite Instability / Middle Aged / multidisciplinary / Mutagens - metabolism / Mutation / Mutation - genetics / Mutation Rate / Peptides - metabolism / Polyketides - metabolism / Russia - epidemiology / Science / Science (multidisciplinary) / Signatures / Thailand - epidemiology / Tumors / Variation / Whole genome sequencing / Yeast