ArticleNature genetics2024
Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer.
Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed.
- Review
- Charting intratumor heterogeneity from bench to bedside.Nature cancer · 2026Review
- Coupled SDE-ODE Modeling of Tumor-Immune Dynamics to Infer Biomarker Release.Bulletin of mathematical biology · 2026Article
- A complete human pancreatic cancer genome.bioRxiv : the preprint server for biology · 2026Article
- Lipid metabolism as a central driver of immune remodeling and therapeutic vulnerability in metastatic colorectal cancer.Lipids in health and disease · 2026Review
- NOUS-209 Off-the-shelf Immunotherapy Has the Potential to Hit Primary and Metachronous Colorectal and Urothelial Cancers in Lynch Syndrome.Molecular cancer therapeutics · 2026Article
- Inherent instability of simple DNA repeats shapes an evolutionarily stable distribution of repeat lengths.Nature communications · 2025Article
- A memory-driven reinforcement learning model of phenotypic adaptation for anticipating therapeutic resistance in prostate cancer.bioRxiv : the preprint server for biology · 2025Article
- Therapeutic targeting of mismatch repair-deficient cancers.Nature reviews. Clinical oncology · 2025Review
- Of Context, Quality, and Complexity: Fine-Combing Tumor Mutational Burden in Immunotherapy-Treated Cancers.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Review
- Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma.Oncogene · 2025Review
- MSH6-proficient crypt foci in MSH6 constitutional mismatch repair deficiency: reversion of a frameshifted coding microsatellite to its wild-type sequence.Familial cancer · 2024Article
- Human and bats genome robustness under COSMIC mutational signatures.bioRxiv : the preprint server for biology · 2024Article
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37 authors.
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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.
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