剑桥大学Douglas J. Winton研究组宣布他们发现了驱动基因突变的衰退塑造了肠道转化的格局。这一研究成果于2025年12月3日发表在国际顶尖学术期刊《自然》上。

通过介导含有Kras或其他常见CRC驱动基因突变的不同小鼠背景下的转化，该课题组发现正常小鼠肠上皮中存在不同的启动事件可以改变转化和克隆选择景观，允许Apc和Ctnnb1中强驱动突变的固定，否则会因负选择而丢失。这些发现，结合他们在人类结直肠癌中与类似启动事件一致的突变模式的证明，表明肠上皮中驱动突变发生的顺序可以决定克隆是正选择还是负选择，并可以塑造随后的肿瘤发育。

据介绍，结直肠癌（CRC）传统上被认为是通过APC肿瘤抑制基因和其他驱动基因的逐步突变，加上正选择克隆的扩增而发展起来的。然而，最近的研究表明，许多癌前病变包括多个表达不同突变APC蛋白的克隆。

附：英文原文

Title: Decay of driver mutations shapes the landscape of intestinal transformation

Author: Loureno, Filipe C., Sadien, Iannish D., Wong, Kim, Adler, Sam, Sawle, Ashley, Santana, Leonor Schubert, Hazelwood, Lee, Giavara, Giada, Nicholson, Anna M., Eldridge, Matthew D., Maka, Noori, Lynch, Gerard, McSorley, Stephen T., Edwards, Joanne, Kemp, Richard, Adams, David J., Winton, Douglas J.

Issue&Volume: 2025-12-03

Abstract: Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1,2,3,4. Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.

DOI: 10.1038/s41586-025-09762-w

Source: https://www.nature.com/articles/s41586-025-09762-w