Christina Curtis研究团队揭示了人类结直肠癌前病变的多克隆来源。2025年11月25日，国际知名学术期刊《自然》发表了这一成果。

为了研究这一点，该课题组人员分析了6例家族性腺瘤样息肉（FAP）患者的正常结肠黏膜、良性和发育不良的癌前息肉以及恶性腺癌（123份样本）。患有FAP的个体具有种系杂合子APC突变，使他们在成年早期易患结直肠癌和许多癌前息肉。全基因组和/或全外显子组测序显示，许多癌前息肉（40%为良性组织学，28%为发育不良）由多个早期分化的遗传谱系组成，与多克隆起源一致。这一结论得到了来自多个息肉患者的单个隐窝的全基因组测序的支持，该测序显示同一病变内的隐窝之间具有有限的突变共享。在某些情况下，多个不同的APC突变共存于一个息肉的不同谱系中，符合多克隆性。这些发现重塑了他们对早期肿瘤事件的理解，表明肿瘤起始可能来自不同突变克隆的聚合。他们还认为，细胞内在的生长优势本身可能不能完全解释肿瘤的发生，强调了微环境和组织水平因素在早期癌症进化中的重要性。

据悉，癌症通常被认为是由单个突变细胞的扩增而形成的。然而，对早期结直肠癌病变的分析表明，肿瘤可能起源于多个遗传上不同的细胞群。在患者中检测多克隆肿瘤起始是具有挑战性的，因为需要在克隆扫描模糊多样性之前对早期病变进行分析。

附：英文原文

Title: Polyclonal origins of human premalignant colorectal lesions

Author: Van Egeren, Debra, Schenck, Ryan O., Khan, Aziz, Horning, Aaron M., Mo, Shanlan, Wei, Clemens L., Esplin, Edward D., Becker, Winston R., Wu, Si, Hanson, Casey, Barapour, Nasim, Jiang, Lihua, Contrepois, Kvin, Lee, Hayan, Nevins, Stephanie A., Guha, Tuhin K., Zhang, Hao, He, Zhen, Ma, Zhicheng, Monte, Emma, Karathanos, Thomas V., Laquindanum, Rozelle, Mills, Meredith A., Chaib, Hassan, Chiu, Roxanne, Jian, Ruiqi, Chan, Joanne, Ellenberger, Mathew, Bahmani, Bahareh, Michael, Basil, Weimer, Annika K., Esplin, D. Glen, Lancaster, Samuel, Shen, Jeanne, Ladabaum, Uri, Longacre, Teri A., Kundaje, Anshul, Greenleaf, William J., Hu, Zheng, Ford, James M., Snyder, Michael P., Curtis, Christina

Issue&Volume: 2025-11-25

Abstract: Cancer is generally thought to be caused by expansion of a single mutant cell1. However, analyses of early colorectal cancer lesions suggest that tumors may instead originate from multiple, genetically distinct cell populations2,3. Detecting polyclonal tumor initiation is challenging in patients, as it requires profiling early-stage lesions before clonal sweeps obscure diversity. To investigate this, we analyzed normal colorectal mucosa, benign and dysplastic premalignant polyps, and malignant adenocarcinomas (123 samples) from six individuals with familial adenomatous polyposis (FAP). Individuals with FAP have a germline heterozygous APC mutation, predisposing them to colorectal cancer and numerous premalignant polyps by early adulthood4. Whole-genome and/or whole-exome sequencing revealed that many premalignant polyps—40% with benign histology and 28% with dysplasia—were composed of multiple genetic lineages that diverged early, consistent with polyclonal origins. This conclusion was reinforced by whole-genome sequencing of single crypts from multiple polyps in additional patients which showed limited sharing of mutations among crypts within the same lesion. In some cases, multiple distinct APC mutations co-existed in different lineages of a single polyp, consistent with polyclonality. These findings reshape our understanding of early neoplastic events, demonstrating that tumor initiation can arise from the convergence of diverse mutant clones. They also suggest that cell-intrinsic growth advantages alone may not fully explain tumor initiation, highlighting the importance of microenvironmental and tissue-level factors in early cancer evolution.

DOI: 10.1038/s41586-025-09930-y

Source: https://www.nature.com/articles/s41586-025-09930-y