LS predisposes the affected persons to cancers, especially to colorectal cancer (CRC) and endometrial cancer (EC), because of an inherited defect in the DNA mismatch repair (MMR) mechanism.

Individuals inherit their predisposing genetic variant from one parent and pass it on to their children with a 50% probability.

Heterozygous germline variants in MMR genes MLH1, MSH2, MSH6, and PMS2, and the deletion of the 3´end of EPCAM (rare) are the identified underlying genetic causes for developing Lynch syndrome. PMS2 and MSH6 have demonstrated the highest population prevalence, whereas MLH1 and MSH2 are linked to the most increased susceptibility to developing cancer.

Typically, the MMR mechanism corrects errors that arise during DNA replication and recombination, and maintains genomic stability in a cell. A functional MMR produces repair proteins, transports them to the nucleus, and forms protein complexes that perform the actual repair. In Lynch syndrome, an inherited gene alteration disrupts this function and  predisposes to cancer.

Defective MMR (dMMR) results in length variation of short tandem nucleotide repeats, microsatellites, which is a hallmark of LS cancers and up to 30% of sporadic cancers.

Pathogenic variants in MLH1 and MSH2 produce a lifetime cancer risk of about 80% to both sexes. In contrast, the lifetime cancer risk in MSH6 carriers is 29% in males and 55% in females due to the increased risk for endometrial cancer.

The recommended age to start colorectal surveillance is 20-35, and 25-35 for gynecologic surveillance. Through increased understanding of the gene-associated differences in risk, clinical management guidelines are turning more gene-specific.

Increased physical activity and reduced body adiposity are associated with decreased cancer risk in the general population, and the same applies to LS.

Universal tumor screening is cost-efficient for selecting potential LS cases, and for overall cancer management after the checkpoint inhibition therapy became available for MMR deficient tumors. Immunohistochemical staining and microsatellite instability analysis are commonly used methods to detect deficient MMR protein expression and/or MSI in a tumor, respectively. Furthermore, MSI phenomenon offers a promising future approach for vaccine-based immunotherapy and immunoprevention of LS-associated cancers.

The major LS-cancers are associated with excellent survival, which is likely to reflect early detection and regular surveillance. However, the current tumor based approaches need to be supplemented with other approaches, such as functional methods capable of diagnosing heritable predisposition also in cases with clinical suspicion of LS but with no identifiable sequence changes, and in unaffected family members. LS CancerDiag provides a novel method, DiagMMR, to study MMR function in non-tumorous cells and recognizing Lynch syndrome without the necessity to find or interpret DNA variants.