英国伦敦大学Marnix Jansen和荷兰乌得勒支大学医学中心Hugo J. G. Snippert共同合作，近期取得重要工作进展，他们研究提出，同聚物切换在错配修复缺陷的结直肠癌中介导适应性突变。相关研究成果2024年7月3日在线发表于《自然—遗传学》杂志上。

据介绍，错配修复（MMR）缺陷癌症通过逐步侵蚀靶基因中的编码同聚物演变而来。值得注意的是，MMR基因MutS同源物6（MSH6）和MutS同源物3（MSH3）也包含编码同聚物，并且这些基因在MMR缺陷癌症中是常见的突变靶点。增量MMR突变对MMR缺陷癌症演化的影响尚不清楚。

研究人员展示了微卫星不稳定性通过随机移码切换在MSH6和MSH3中的超可变单核苷酸同聚物运行来调节DNA修复。自发的突变和恢复调节亚克隆突变率、突变偏差以及HLA和新抗原多样性。患者来源的类器官验证了这些观察结果，并显示在没有免疫选择的情况下，MMR同聚物序列漂移回阅读框，这表明高突变率具有适应性成本。结合实验和模拟研究表明，亚克隆免疫选择有利于增量MMR突变。

总之，这一数据表明，MMR缺陷的结直肠癌通过适应亚克隆突变率和多样性，来迎合免疫选择从而加剧肿瘤内异质性。

附：英文原文

Title: Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer

Author: Kayhanian, Hamzeh, Cross, William, van der Horst, Suzanne E. M., Barmpoutis, Panagiotis, Lakatos, Eszter, Caravagna, Giulio, Zapata, Luis, Van Hoeck, Arne, Middelkamp, Sjors, Litchfield, Kevin, Steele, Christopher, Waddingham, William, Patel, Dominic, Milite, Salvatore, Jin, Chen, Baker, Ann-Marie, Alexander, Daniel C., Khan, Khurum, Hochhauser, Daniel, Novelli, Marco, Werner, Benjamin, van Boxtel, Ruben, Hageman, Joris H., Buissant des Amorie, Julian R., Linares, Josep, Ligtenberg, Marjolijn J. L., Nagtegaal, Iris D., Lacl, Miangela M., Moons, Leon M. G., Brosens, Lodewijk A. A., Pillay, Nischalan, Sottoriva, Andrea, Graham, Trevor A., Rodriguez-Justo, Manuel, Shiu, Kai-Keen, Snippert, Hugo J. G., Jansen, Marnix

Issue&Volume: 2024-07-03

Abstract: Mismatch repair (MMR)-deficient cancer evolves through the stepwise erosion of coding homopolymers in target genes. Curiously, the MMR genes MutS homolog 6 (MSH6) and MutS homolog 3 (MSH3) also contain coding homopolymers, and these are frequent mutational targets in MMR-deficient cancers. The impact of incremental MMR mutations on MMR-deficient cancer evolution is unknown. Here we show that microsatellite instability modulates DNA repair by toggling hypermutable mononucleotide homopolymer runs in MSH6 and MSH3 through stochastic frameshift switching. Spontaneous mutation and reversion modulate subclonal mutation rate, mutation bias and HLA and neoantigen diversity. Patient-derived organoids corroborate these observations and show that MMR homopolymer sequences drift back into reading frame in the absence of immune selection, suggesting a fitness cost of elevated mutation rates. Combined experimental and simulation studies demonstrate that subclonal immune selection favors incremental MMR mutations. Overall, our data demonstrate that MMR-deficient colorectal cancers fuel intratumor heterogeneity by adapting subclonal mutation rate and diversity to immune selection.

DOI: 10.1038/s41588-024-01777-9

Source: https://www.nature.com/articles/s41588-024-01777-9