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

Area of Science:

• Oncology
• Genetics
• Cancer Biology

Background:

• Mismatch repair (MMR)-deficient cancers accumulate mutations by eroding coding homopolymers.
• MMR genes MSH6 and MSH3 contain homopolymers and are frequently mutated in these cancers.

Purpose of the Study:

• To investigate the impact of incremental MMR mutations on MMR-deficient cancer evolution.
• To understand how microsatellite instability influences DNA repair and tumor heterogeneity.

Main Methods:

• Analysis of coding homopolymers in MSH6 and MSH3.
• Stochastic frameshift switching in mononucleotide runs.
• Patient-derived organoids and simulation studies.
• Assessment of mutation rate, bias, and neoantigen diversity.

Main Results:

• Microsatellite instability toggles hypermutable homopolymer runs in MSH6 and MSH3.
• Spontaneous mutation and reversion modulate subclonal mutation rates and neoantigen diversity.
• MMR homopolymer sequences revert in the absence of immune selection, indicating a fitness cost.
• Subclonal immune selection favors incremental MMR mutations.

Conclusions:

• MMR-deficient colorectal cancers adapt subclonal mutation rates and diversity in response to immune selection.
• This adaptation fuels intratumor heterogeneity, driving cancer evolution.