Díaz-Gay Marcos, Dos Santos Wellington, Moody Sarah, Kazachkova Mariya, Abbasi Ammal, Steele Christopher D, Vangara Raviteja, Senkin Sergey, Wang Jingwei, Fitzgerald Stephen, Bergstrom Erik N, Khandekar Azhar, Otlu Burçak, Abedi-Ardekani Behnoush, de Carvalho Ana Carolina, Cattiaux Thomas, Penha Ricardo Cortez Cardoso, Gaborieau Valérie, Chopard Priscilia, Carreira Christine, Cheema Saamin, Latimer Calli, Teague Jon W, Mukeriya Anush, Zaridze David, Cox Riley, Albert Monique, Phouthavongsy Larry, Gallinger Steven, Malekzadeh Reza, Niavarani Ahmadreza, Miladinov Marko, Erić Katarina, Milosavljevic Sasa, Sangrajrang Suleeporn, Curado Maria Paula, Aguiar Samuel, Reis Rui Manuel, Reis Monise Tadin, Romagnolo Luis Gustavo, Guimarães Denise Peixoto, Holcatova Ivana, Kalvach Jaroslav, Vaccaro Carlos Alberto, Piñero Tamara Alejandra, Świątkowska Beata, Lissowska Jolanta, Roszkowska-Purska Katarzyna, Huertas-Salgado Antonio, Shibata Tatsuhiro, Shiba Satoshi, Sangkhathat Surasak, Chitapanarux Taned, Roshandel Gholamreza, Ashton-Prolla Patricia, Damin Daniel C, de Oliveira Francine Hehn, Humphreys Laura, Lawley Trevor D, Perdomo Sandra, Stratton Michael R, Brennan Paul, Alexandrov Ludmil B
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA.
Department of Bioengineering, University of California San Diego, La Jolla, CA, USA.
Nature. 2025 Apr 23. doi: 10.1038/s41586-025-09025-8.
Incidence rates of colorectal cancer vary geographically and have changed over time. 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. 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, 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.
结直肠癌的发病率在不同地区存在差异，并且随时间发生了变化。值得注意的是，在过去二十年中，影响50岁以下个体的早发性结直肠癌的发病率在许多国家翻了一番。这种增加的原因尚不清楚。在这里，我们通过检查来自11个国家的981个结直肠癌基因组，研究突变过程是否导致了地理和年龄相关的差异。在微卫星不稳定的癌症中未发现重大差异，但在802例微卫星稳定的病例中观察到了突变负担和特征的变化。多种特征，大多数病因不明，在阿根廷、巴西、哥伦比亚、俄罗斯和泰国呈现出不同的流行率，表明诱变暴露水平在地理上存在差异。由细菌产生的诱变剂大肠杆菌素引起的特征SBS88和ID18，在结直肠癌发病率较高的国家中具有更高的突变负荷。SBS88和ID18在早发性结直肠癌中也更为富集，在40岁之前被诊断出的个体中比70岁以上的个体中常见3.3倍，并且在结直肠癌发展的早期就留下了印记。大肠杆菌素暴露还与APC驱动突变有关，在大肠杆菌素阳性病例中，ID18约占APC驱动插入缺失的25%。这项研究揭示了结直肠癌突变过程中的地理和年龄相关变异，并表明早年接触产生大肠杆菌素的细菌可能导致早发性结直肠癌发病率的增加。
