错配修复（MMR）缺陷的癌症是通过靶基因中编码同聚物的逐步侵蚀而进化的。奇怪的是，MMR 基因 MutS 同源物 6 (MSH6) 和 MutS 同源物 3 (MSH3) 也含有编码同聚物，这些是 MMR 缺陷癌症中常见的突变靶点。增量 MMR 突变对 MMR 缺陷癌症进化的影响尚不清楚。在这里，我们证明微卫星不稳定性通过随机移码切换切换 MSH6 和 MSH3 中超可变单核苷酸均聚物的运行来调节 DNA 修复。自发突变和回复调节亚克隆突变率、突变偏倚以及 HLA 和新抗原多样性。源自患者的类器官证实了这些观察结果，并表明在没有免疫选择的情况下，MMR 均聚物序列会漂移回阅读框，这表明突变率升高的适应性成本。实验和模拟相结合的研究表明，亚克隆免疫选择有利于增量 MMR 突变。总体而言，我们的数据表明，MMR 缺陷的结直肠癌通过调整亚克隆突变率和多样性来适应免疫选择，从而加剧肿瘤内异质性。© 2024。作者。

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.© 2024. The Author(s).