A NEW study has uncovered a mechanism that drives the evolution of mismatch repair (MMR)-deficient colorectal cancer, a type of cancer known for its high mutation rates. The research focuses on the role of homopolymer sequences which are stretches of repeated DNA bases in the genes involved in DNA repair, specifically MSH6 and MSH3. These sequences are highly prone to mutations in MMR-deficient cancers, leading to microsatellite instability (MSI).
The study reveals that these homopolymer sequences act as “switches” that can toggle the mutation rates within the cancer cells. As these sequences mutate and revert, they create a dynamic environment where the mutation rate and the types of mutations that occur can change over time. This process not only affects the genetic diversity within the tumour but also impacts how the immune system interacts with the cancer.
In experiments using patient-derived organoids, miniature, lab-grown versions of the tumours. The researchers found that these homopolymer sequences could drift back into their normal, functional state in the absence of immune pressure. This suggests that while high mutation rates may help the cancer adapt and survive in the face of immune attacks, there is a fitness cost associated with maintaining such high levels of genetic instability.
The findings from this study provide new insights into how MMR-deficient colorectal cancers evolve, highlighting the intricate balance between mutation rates, immune selection, and tumour survival. This research not only advances the understanding of cancer biology but also points to potential new strategies for targeting these highly mutable cancers by exploiting their inherent weaknesses in DNA repair.
Aleksandra Zurowska, EMJ
Reference
Kayhanian H et al. Homopolymer switches mediate adaptive mutability in mismatch repair-deficient colorectal cancer. Nat Genet. 2024;56:1420–33.
