Genetic Variants of UGP2 and FBP2 in the Glycolysis Pathway Independently Predict Survival of Patients with HBV-Related Hepatocellular Carcinoma.

Purpose: Glycolysis is a group of metabolic processes that may alter tumor microenvironment to have effects on the growth and proliferation of tumor cells, including liver cancer. However, the effect of genetic variants in glycolysis pathway genes in survival of patients with hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) remains unclear.

Methods: We employed multivariable Cox proportional hazards regression analyses to estimate associations between genetic variants in 240 glycolysis pathway genes and overall survival (OS) of 866 patients with HBV-HCC, and we also used false positive report probability for multiple testing corrections.

Results: We found that UGP2 rs4293553 G allele was significantly associated with a better OS of HBV-HCC patients [hazards ratio (HR) = 0.73, 95% confidence interval (CI) = 0.62-0.86, P < 0.001], and that FBP2 rs635087 G allele was significantly associated with a worse OS in these patients (HR = 1.38, 95% CI = 1.18-1.61, P < 0.001). The expression quantitative trait loci analysis using the GTEx database showed that the rs635087 G allele was significantly correlated with reduced FBP2 mRNA expression levels in normal liver tissues (P < 0.001), but such a correlation was not significant for the rs4293553 G allele. Functional annotation results indicate that these two single nucleotide polymorphisms have potential biological functions, providing biological plausibility for the observed associations. In addition, the mRNA expression levels of both UGP2 and FBP2 were significantly lower in HCC tissues than in normal liver tissues (both P < 0.001), and high expression levels of both UGP2 and FBP2 were significantly associated with favorable survival in HCC patients (both P < 0.001).

Discussion: Our findings suggested that genetic variants in glycolysis pathway genes may serve as novel prognostic markers for survival of patients with HBV-HCC, especially FBP2 rs635087, if validated in additional larger studies and functional investigations.