A multilevel perspective on MSH6 ‐associated Lynch syndrome: Integrating molecular, biological, and clinical insights

Abstract Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by a germline pathogenic variant in one of the mismatch repair (MMR) genes. Among these, MSH6‐ associated LS represents a distinct subtype with unique molecular and clinical characteristics. Despite its relatively high prevalence (~1 in 758 individuals) compared with MLH1‐ (1 in 1946) and MSH2‐ associated LS (1 in 2841), MSH6 ‐associated LS remains underrepresented in research and clinical guidelines. To bridge this knowledge gap, we reviewed current literature on molecular, biological, and clinical aspects of MSH6 ‐associated LS. From a biological perspective, loss of MSH6 function results in a relatively low degree of microsatellite instability and potentially slower tumor progression compared with other LS subtypes. Nevertheless, tumor immunogenicity of MSH6‐ associated colorectal cancers appears preserved, supporting responsiveness to immune checkpoint inhibitors. Clinically, pathogenic MSH6 (path_ MSH6) variant carriers have a unique tumor spectrum, characterized by a relatively lower colorectal cancer penetrance (~8. 1%–44%) compared with path_ MLH1 and path_ MSH2 carriers, but a relatively high endometrial cancer risk (~16%–44%), with a median age of onset approximately a decade later than that observed for path_ MLH1 or path_ MSH2 carriers. Phenotypic heterogeneity among path_ MSH6 carriers may reflect contributions from modifier genes, environmental exposures, microbiome composition and/or the individual's HLA type. Recognition of the distinct biology of MSH6‐ associated LS and its clinical implications highlights the importance of gene‐specific precision in clinical care, such as initiating colonoscopy surveillance at a later age (30–35 years) and performing it every 2–3 years.