Cancer risks for MSH6 pathogenic variant carriers.

Area of Science:

• Genetics and Genomics
• Oncology
• Hereditary Cancer Syndromes

Background:

• Lynch syndrome (LS) is a hereditary cancer syndrome linked to DNA mismatch repair gene pathogenic variants (PVs), including MSH6.
• MSH6-associated LS (MSH6-LS) increases cancer risk, but precise estimates, especially for non-colorectal cancers, are uncertain, hindering personalized clinical guidance.

Purpose of the Study:

• To refine cancer risk estimates for individuals carrying pathogenic or likely pathogenic MSH6 variants.
• To provide age- and sex-specific risk data for MSH6 PV carriers to inform clinical management.

Main Methods:

• Retrospective cohort study of 1117 MSH6 PV carriers from 360 Dutch families (1995-2020).
• Cancer diagnoses confirmed via medical records; age- and sex-specific cumulative risks (CRs) and hazard ratios (HRs) calculated using segregation analysis, adjusted for ascertainment bias.

Main Results:

• By age 80, cumulative CRC risk was 36% for males and 21% for females. Endometrial cancer CR was 23% in females.
• Elevated lifetime risks observed for ovarian (6.4%), urinary tract (males 10.1%, females 4.1%), and biliary tract cancers (males 4.9%, females 4.2%).
• No increased risk for prostate or breast cancer; low CRC risk at age 40 (males 0.2%, females 0.9%).

Conclusions:

• Refined, age- and sex-specific risk estimates for MSH6 PV carriers enhance understanding of MSH6-associated LS.
• These estimates support tailored surveillance strategies, including delayed CRC screening and individualized counseling on risk-reducing surgery for women.