Colonoscopy screening outcomes in Lynch syndrome and differential colorectal cancer paths among MLH1 / MSH2 carriers

BACKGROUD: Lynch syndrome, caused by pathogenic variants in mismatch repair genes increases the risk of colorectal cancer, which remains elevated even under active colonoscopy surveillance. A deeper understanding of the underlying mechanisms driving CRC development under colonoscopy surveillance in individuals with LS is crucial for evaluating its effectiveness. The goal of this study is to better understand the differential patterns of CRC development focusing more specifically on MLH1 and MSH2 carriers. METHODS: Patients with Lynch syndrome were identified through the Familial Gastrointestinal Cancer Registry in the Zane Cohen Centre at Mount Sinai hospital, Toronto. This study proposed a general model integrating colonoscopy screening visits, adenoma counts, and CRC occurrence (a joint model) and which accounts for their interdependencies when modelling CRC risk. RESULTS: More frequent colonoscopy screenings resulting in an increased number of adenomas detected effectively reduces CRC risk in those with a pathogenic variant in MSH2, potentially due to a risk-reducing effect. MLH1 carriers did not experience the same benefit. After 10-year follow-up, among individuals with adenomas, CRC risk was much higher in MLH1 compared to MSH2 carriers, 7.9% [95% CI = 3.9-15.8%] vs. 4.0% [95% CI = 1.6-9.6%] in males and 4.2% [95% CI = 2.2-8.2%] vs. 1.6% [95% CI = 0.7-3.5%] in females. CONCLUSIONS: Our study identified differences in MLH1 and MSH2 cancer development which may suggest distinct mechanisms impacting CRC. The inverse relationship between adenoma detection and CRC risk in MSH2 carriers enhances our understanding of the adenoma-carcinoma sequence, while the lack of association in MLH1 carriers suggests alternative carcinogenic pathways requiring further study.