Journal: International journal of cancer
This review focuses on the distinct biology and clinical behavior of Lynch syndrome due to pathogenic variants in MSH6.
Key points:
- Epidemiology and under-recognition
- MSH6-related Lynch syndrome is relatively common (estimated prevalence about 1 in 758), yet it is underrepresented in research and guidelines compared with MLH1- and MSH2-related disease.
- Biology and tumor characteristics
- Loss of MSH6 leads to a lower degree of microsatellite instability and likely slower tumor evolution than seen in other Lynch genes.
- Despite this, colorectal cancers arising in this setting remain immunogenic, supporting sensitivity to immune checkpoint inhibitors.
- Cancer risks and phenotype
- Colorectal cancer risk in MSH6 carriers is lower and more variable (~8.1%–44%) than in MLH1/MSH2 carriers.
- Endometrial cancer risk is relatively high (~16%–44%).
- Median age of onset for these cancers is roughly 10 years later than for MLH1/MSH2 carriers.
- There is marked phenotypic heterogeneity, potentially influenced by genetic modifiers, environment, microbiome, and HLA type.
- Clinical implications
- Because of the later onset and different risk profile, the authors support gene-specific management: for MSH6 carriers, colonoscopy can reasonably start later (around 30–35 years) and be repeated every 2–3 years, rather than following a one-size-fits-all Lynch protocol.
Overall, the article argues for treating MSH6-associated Lynch syndrome as a distinct clinical entity and tailoring surveillance and management accordingly.