Wei_2025_J.Cancer.Res.Clin.Oncol_151_170

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with both genetic and environmental risk factors. The PON1 rs854560 (L55M) polymorphism has been implicated in cancer susceptibility through its role in oxidative stress regulation, but its association with CRC remains unclear, particularly in Asian populations. AIM: This study aimed to investigate the association between the PON1 rs854560 polymorphism and CRC susceptibility in a Chinese cohort, while assessing its impact on PON1 expression and enzymatic activity. METHOD: A case-control study was conducted on 1,003 CRC patients and 1,303 healthy controls. The impact of the Pon1-rs854560 SNP was assessed by comparing the genotypes of individuals diagnosed with CRC to those of controls without the disease. RESULTS: Genotype distribution showed slight differences between the case and control groups. The frequency of the AA genotype was slightly lower in the case group (91.72%) than in the control group (93.71%). The AT genotype was observed at similar frequencies in both groups (8.28% in the case group and 6.14% in the control group). Notably, the TT genotype was absent in the case group but present in 0.15% of the control group. Genotype combination analysis suggested that individuals carrying the AT + TT genotype (8.28%) had a higher susceptibility to CRC compared to those with the AA + AT genotype (100%). Allele frequency analysis revealed a slightly higher frequency of allele T in the case group (8.28%) than in the control group (6.45%). Additionally, lower PON1 mRNA and protein expression were associated with CRC progression, including features such as poorer differentiation, deeper tumor invasion, and vascular, nerve, and lymphatic metastasis. CONCLUSION: The PON1 rs854560 polymorphism influences CRC risk in Chinese individuals, likely through reduced PON1 expression and detoxification capacity. These findings highlight its potential as a genetic biomarker for CRC susceptibility and suggest PON1's role in tumor progression. Further studies should validate these associations in diverse populations and explore therapeutic strategies targeting PON1 activity.