ENOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib.

Abstract

230 Background: Cancer cells adapt to hypoxic microenvironment through the activation of many molecules, including endothelial nitric oxide synthase (eNOS). Sorafenib, by blocking the vascular endothelial growth factor receptors (VEGFRs), induces an inhibition of eNOS activity with a consequent decrease of the production of nitric oxide (NO). NO is associated with an increase of tumor angiogenesis, tumor invasion and metastasis formation. In our study we analysed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma treated with sorafenib. Methods: From a database of 257 patients diagnosed with hepatocellular carcinoma from 2004 to 2014, we selected 54 patients who received sorafenib. Peripheral blood samples or FFPE tumor tissues were available for DNA extraction and genotyping analysis. Three eNOS polymorphisms (eNOS +894 G/T, eNOS VNTR 27bp 4a/b, eNOS -786 C/T) were analyzed by direct sequencing or Real Time PCR method. We analyzed 21 patients for the VNTR 4a/b polymorphism and 32 patients for -786 C/T polymorphism. All the candidate genotypes were evaluated to identify a potential correlation with overall survival (OS) (log-rank test). Results: With regard to eNOS VNTR it was observed that patients carrying the b allele (5 repetitions of 27bp) both in homozygosity (4bb) and in heterozygosity (4ab) were associated with a better OS. The variants 4aa (4 repeats of 27bp in homozygosity), 4ab and 4bb, were associated with a median OS of 5.7, 13.9 and 23.6 months, respectively (p = 0.016). For eNOS-786 the presence of the T allele both in homozygosity (TT) and in heterozygosity(TC) was associated with a statistically significant longer OS with respect to patients with CC genotype (15.6 versus 13.9 months, respectively, p = 0.031). No correlations were observed in relation to PFS (p = 0.494). Conclusions: eNOS VNTR and eNOS -786 could represent prognostic markers in patients with advanced hepatocellular carcinoma treated with sorafenib.