Genetics of Lynch Syndrome and Clinical Implications

Lynch Syndrome (LS) is a hereditary disorder inherited in an autosomal dominant pattern and caused by germline mutations in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, PMS2, and EPCAM. These genes play an important role in maintaining genomic integrity by correcting replication errors during DNA synthesis.

LS contributes to approximately 3% of colorectal cancers (CRC) and endometrial cancers (EC). It is associated with an increased risk of malignancies in multiple organs, including the stomach, ovaries, urinary tract, and small bowel. Tumors linked to LS typically exhibit MMR deficiency (dMMR) and high levels of microsatellite instability (MSI).

Prevalence:

Population estimates suggest that about 1 in 279 individuals carry pathogenic variants in MMR genes. Mutations in PMS2 and MSH6 are more frequent but exhibit lower penetrance compared to MLH1 and MSH2. Certain populations, such as Icelanders, have higher carrier rates due to founder mutations. LS-related cancers generally manifest earlier than sporadic cancers, typically between 40 and 60 years of age.

MMR proteins detect and repair mismatches during DNA replication by recruiting excision machinery and resynthesizing accurate strands. Dysfunctional MMR results in MSI, a defining characteristic of LS tumors. Additionally, MMR proteins play roles beyond repair, including signaling apoptosis and preventing chromosomal rearrangements through recombination inhibition.

Accurate diagnosis requires identifying pathogenic variants in MMR genes or EPCAM, often through sequencing techniques that include assessments for large genomic rearrangements. Multigene panel testing improves detection rates but may identify variants of uncertain significance. Liquid biopsies and next-generation sequencing (NGS) of tumor tissues enhance sensitivity in distinguishing LS from sporadic cancers and monitoring treatment progress.

Gene-specific surveillance protocols recommend initiating colonoscopy at 20–25 years for MLH1/MSH2 carriers and 30–35 years for those with MSH6/PMS2 mutations. Screening intervals are adjusted to individual risk and typically range from 1 to 3 years.

Preventive and Treatment Strategies:

• Lifestyle changes, such as physical activity, weight management, and aspirin intake (≥75–100 mg/day), effectively reduce CRC risk, with outcomes varying by sex and genetic mutation.
• Immunotherapy, particularly PD-1 blockade, has demonstrated remarkable success in treating metastatic and locally advanced MSI-H cancers.
• Surgical management of CRC is tailored to genetic risk, with extended resections recommended for MLH1 and MSH2 carriers to reduce the risk of metachronous cancers.