法国基因组流行病学处Michael R. Stratton研究组揭示了结直肠癌突变过程中的地理和年龄差异。相关论文于2025年4月23日发表在《自然》杂志上。

该研究团队通过检查来自11个国家的981个结直肠癌基因组来研究突变过程是否会导致地理和年龄相关的差异。在微卫星不稳定癌症中没有发现重大差异，但在802例微卫星稳定病例中观察到突变负担和特征的变化。在阿根廷、巴西、哥伦比亚、罗马尼亚和泰国，多数病因不明的多重特征显示出不同的流行率，这表明在地理上存在不同程度的诱变暴露。由细菌产生的突变原colibactin引导的特征SBS88和ID18在结直肠癌发病率较高的国家具有较高的突变负荷。SBS88和ID18在早发性结直肠癌中也很丰富，在40岁之前诊断的个体中，SBS88和ID18的发生率是70岁以上人群的3.3倍，并且在结直肠癌发展的早期就有印记。大肠杆菌素暴露与APC驱动突变进一步相关，在大肠杆菌素阳性病例中，约25%的APC驱动基因由ID18引起。该研究揭示了结直肠癌突变过程的地理和年龄相关差异，并提示生命早期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上升。

研究人员表示，结直肠癌的发病率因地域而异，且随时间而变化。值得注意的是，在过去二十年中，影响50岁以下人群的早发性结直肠癌发病率在许多国家翻了一番。这种增长的原因尚不清楚。

附：英文原文

Title: Geographic and age variations in mutational processes in colorectal cancer

Author: Daz-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, Burak, Abedi-Ardekani, Behnoush, de Carvalho, Ana Carolina, Cattiaux, Thomas, Penha, Ricardo Cortez Cardoso, Gaborieau, Valrie, 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, Eri, Katarina, Milosavljevic, Sasa, Sangrajrang, Suleeporn, Curado, Maria Paula, Aguiar, Samuel, Reis, Rui Manuel, Reis, Monise Tadin, Romagnolo, Luis Gustavo, Guimares, Denise Peixoto, Holcatova, Ivana, Kalvach, Jaroslav, Vaccaro, Carlos Alberto, Piero, Tamara Alejandra, witkowska, 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.

Issue&Volume: 2025-04-23

Abstract: Colorectal cancer incidence rates vary geographically and have changed over time1. Notably, in the past two decades, the incidence of early-onset colorectal cancer, affecting individuals under the age of 50 years, 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 etiologies, 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 diagnosed before age 40 than in those over 70, and were imprinted early during colorectal cancer development. Colibactin exposure was further linked to APC driver mutations, with ID18 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 early-life mutagenic exposure to colibactin-producing bacteria may contribute to the rising incidence of early-onset colorectal cancer.

DOI: 10.1038/s41586-025-09025-8

Source: https://www.nature.com/articles/s41586-025-09025-8