PDF(Pubmed)
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.
摘要：
错配修复(MMR)缺陷型癌症通过靶基因中编码均聚物的逐步侵蚀而演变。奇怪的是,MMR基因MutS同源物6（MSH6）和MutS同源物3（MSH3）也包含编码均聚物，这些是MMR缺陷型癌症的常见突变靶标。增加的MMR突变对MMR缺陷型癌症进化的影响是未知的。在这里，我们表明微卫星不稳定性通过随机移码切换在MSH6和MSH3中切换超可变单核苷酸均聚物运行来调节DNA修复。自发突变和逆转调节亚克隆突变率，突变偏倚与HLA和新抗原多样性。患者来源的类器官证实了这些观察结果，并表明MMR均聚物序列在没有免疫选择的情况下漂移回阅读框，表明突变率升高的健身成本。结合的实验和模拟研究表明，亚克隆免疫选择有利于增加MMR突变。总的来说,我们的数据表明,MMR缺陷型结直肠癌通过使亚克隆突变率和多样性适应免疫选择而助长了瘤内异质性.
