SNP association study in PMS2-associated Lynch syndrome

Area of Science:

• Genetics
• Oncology
• Cancer Epidemiology

Background:

• Lynch syndrome (LS) patients face elevated colorectal cancer (CRC) risk.
• Phenotypic variability in LS may be influenced by common susceptibility loci from Genome-Wide Association Studies (GWAS).
• Prior research on GWAS single nucleotide polymorphisms (SNPs) in LS primarily focused on MLH1, MSH2, and MSH6 carriers with inconsistent findings.

Purpose of the Study:

• To investigate the influence of GWAS SNPs on CRC risk specifically in individuals with PMS2 mutations.
• To determine if common genetic variants modify CRC susceptibility in the PMS2 mutation carrier group.

Main Methods:

• A cohort study involving 507 PMS2 mutation carriers (124 with CRC) was conducted.
• Participants were genotyped for 24 GWAS SNPs.
• Weighted Cox regression analysis and bootstrap cross-validation were used to calculate hazard ratios (HRs) and assess discrimination, correcting for ascertainment bias.

Main Results:

• No individual SNPs showed significant associations with CRC risk (HR < 2).
• Male carriers of allele A at rs1321311 (6p21.31) exhibited a potential increased CRC risk (HR = 2.1).
• A polygenic risk score (PRS) demonstrated a higher HR (2.6) for the highest quartile but lacked discriminative ability (c-statistic = 0.52).

Conclusions:

• Previously identified GWAS SNPs do not appear to modify CRC risk in PMS2 mutation carriers.
• Current common genetic variants do not sufficiently stratify CRC risk within the PMS2 LS population.
• Larger studies are required to identify genetic factors for improved risk stratification in Lynch syndrome patients.