Associations Between Mutations in MSH6 and PMS2 and Risk of Surveillance-detected Colorectal Cancer

Area of Science:

• Oncology
• Genetics
• Gastroenterology

Background:

• Lynch syndrome is the primary inherited cause of colorectal cancer (CRC).
• Optimizing surveillance strategies requires contemporary, mutation-specific CRC risk estimates for Lynch syndrome patients.

Purpose of the Study:

• To assess the overall and mutation-specific risk of colorectal cancer (CRC) in individuals with Lynch syndrome undergoing surveillance colonoscopies.
• To provide data for refining surveillance protocols based on genetic variants.

Main Methods:

• A prospective national cohort study in New Zealand involving 381 individuals with Lynch syndrome (MLH1, MSH2, MSH6, PMS2 variants).
• Annual colonoscopies were offered starting at age 25; analysis included those with at least two colonoscopies before December 31, 2017.
• Exclusion criteria included prior colonic resection, CRC history, or CRC diagnosis at the initial colonoscopy.

Main Results:

• Over 2296 person-years and 2061 colonoscopies, 18 patients developed CRC.
• Cumulative CRC risks by age 70 varied by mutation: MLH1 (17.7%), MSH2 (17.8%), and MSH6 (8.5%).
• CRC risk was significantly lower for MSH6 variants compared to MLH1 (HR 0.2, P = .02). 94% of CRCs were diagnosed at early stages (0-II), with no CRC-related mortality.

Conclusions:

• Colorectal cancer risk is significantly lower in Lynch syndrome patients with MSH6 or PMS2 mutations compared to MLH1 mutations.
• Incomplete resection of adenomatous polyps may contribute to approximately one-third of colorectal cancers detected during surveillance.