Geographic and age variations in mutational processes in colorectal cancer
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.
Article Details
Authors (63)
Marcos Díaz-Gay
Wellington dos 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 de Carvalho
Thomas Cattiaux
Ricardo Cortez Cardoso Penha
Valerie 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 de Oliveira
Laura Humphreys
Trevor D. Lawley
Sandra Perdomo
Michael R. Stratton
Paul Brennan
Ludmil B. Alexandrov