Potentially Functional Variants of DCTD and ENTPD2 in the Metabolism of Nucleotide Pathway Genes Predict Survival of HBV-Related Hepatocellular Carcinoma Patients.

Purpose: Nucleotide metabolism plays a critical role in cancer development, but the prognostic significance of genetic variants in nucleotide metabolism genes for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients remains unclear. Methods: We performed Cox proportional hazards regression analyses to evaluate the association between genetic variants in 94 nucleotide metabolism-related genes and overall survival (OS) in 866 HBV-HCC patients. To assess the potential biological relevance of the identified variants, the Bayesian false discovery probability and false-positive report probability were applied for multiple testing correction. Results: Two independent SNPs, DCTD rs17074255 G>A (HR = 1.22, 95% CI: 1.06-1.40, p = 0.005) and ENTPD2 rs3763662 G>A (HR = 1.18, 95% CI: 1.03-1.34, p = 0.015), were significantly associated with OS. A significant dose-dependent association between the number of risk genotypes and poorer OS was observed (Ptrend < 0.001). Luciferase reporter assays demonstrated allele-specific regulatory effects of rs3763662 on ENTPD2 expression (p < 0.001). DCTD and ENTPD2 mRNA expression levels were significantly elevated in HCC tumors in the UALCAN database and in our 103 paired samples. Higher expression levels of both genes were associated with poorer survival in the TCGA cohort (p = 0.003 and p < 0.001). Conclusions: Our findings suggest that ENTPD2 rs3763662 (supported by direct functional evidence) and DCTD rs17074255 (supported by eQTL and expression associations) may serve as potential prognostic indicators for HBV-HCC through the regulation of mRNA expression. These findings provide new insights into the role of nucleotide metabolism-related genetic variation in HBV-HCC progression and may facilitate prognostic assessment, pending replication in independent cohorts.