Minimally Invasive Biomarkers to Improve Endoscopic Cancer Surveillance in Individuals With Lynch Syndrome: a Prospective Institutional Study

Rationale: Lynch syndrome is caused by germline pathogenic variants in one of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, or EPCAM through MSH2 inactivation). Tumors arising in LS carriers characteristically exhibit microsatellite instability, which develops early during colorectal carcinogenesis, together with loss of expression of one or more MMR proteins on immunohistochemistry. MMR deficiency predisposes to frameshift mutations at coding mononucleotide repeats, and these mutations have recently been detected in the circulation of patients with MSI-high/MMR-deficient tumors.

In Italy, more than 50,000 new colorectal cancer cases are diagnosed each year, approximately 3-5% of which are associated with LS. Although LS is relatively uncommon, it is associated with a markedly increased lifetime risk of CRC, including an approximately 14-fold higher risk of developing CRC before the age of 50 compared with the general population, as well as an increased risk of metachronous tumors. Colonoscopic surveillance starting at 20-25 years of age and repeated every 1-2 years is currently the only established strategy to reduce CRC morbidity and mortality. However, colonoscopy is invasive, costly, and may become burdensome after years of lifelong surveillance, potentially affecting adherence. Moreover, interval cancers may develop between scheduled examinations.

Minimally invasive biomarkers capable of detecting early neoplastic changes could improve risk stratification, personalize surveillance intervals, and increase patient compliance. Circulating tumor-derived nucleic acids, including circulating tumor DNA and microRNAs, represent promising biomarkers for CRC detection and monitoring. MSI and MMR-related frameshift mutations arise early during tumorigenesis and may be detected by liquid biopsy, while circulating miRNAs are highly stable and become dysregulated during early CRC development. Stool represents a non-invasive source of tumor-derived DNA, miRNAs, and microbial signals directly related to colorectal epithelial biology. Analysis of fecal DNA may improve the detection of early MMR-deficient lesions by identifying characteristic frameshift mutations, while fecal miRNA and gut microbiome profiling may provide complementary signatures associated with colorectal carcinogenesis.

Preliminary institutional data from study INT 118/21 support the feasibility of liquid biopsy-based MSI analysis and miRNA profiling in LS patients undergoing endoscopic surveillance. These findings provide the rationale for a larger prospective observational study integrating plasma-, stool-, and urine-based molecular biomarkers with standard surveillance colonoscopy.

Study design and procedures: this is a prospective, longitudinal, observational study enrolling adult patients (≥18 years) with genetically confirmed Lynch Syndrome followed at the Unit of Hereditary Digestive Tract Tumors, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.