ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib

Abstract

Sorafenib represents the standard of care for advanced hepatocellular carcinoma (HCC), even though a large number of patients have reported limited efficacy. The aim of the present study was to evaluate the prognostic value of single-nucleotide polymorphisms on angiopoietin-2 (ANGPT2) and endothelial-derived nitric oxide synthase (NOS3) genes in 135 patients with advanced HCC receiving sorafenib. Eight ANGPT2 polymorphisms were analyzed by direct sequencing in relation to overall survival (OS) and progression-free survival (PFS). In univariate analysis, ANGPT2rs55633437 and NOS3 rs2070744 were associated with OS and PFS. In particular, patients with ANGPT2rs55633437 TT/GT genotypes had significantly lower median OS (4.66 vs. 15.5 months, hazard ratio (HR) 4.86, 95% CI 2.73–8.67, p < 0.001) and PFS (1.58 vs. 6.27 months, HR 4.79, 95% CI 2.73–8.35, p < 0.001) than those homozygous for the G allele. Moreover, patients with NOS3 rs2070744 TC/CC genotypes had significantly higher median OS (15.6 vs. 9.1 months, HR 0.65, 95% CI 0.44–0.97; p = 0.036) and PFS (7.03 vs. 3.5 months, HR 0.43, 95% CI 0.30–0.63; p < 0.001) than patients homozygous for the T allele. Multivariate analysis confirmed these polymorphisms as independent prognostic factors. Our results suggest that ANGPT2rs55633437 and NOS3 rs2070744 polymorphisms could identify a subset of HCC patients more resistant to sorafenib.

Association of Genetic Variants in ANGPT/TEK and VEGF/VEGFR with Progression and Survival in Head and Neck Squamous Cell Carcinoma Treated with Radiotherapy or Radiochemotherapy

“…A relationship between the A allele and higher circulating ANGPT2 levels was observed in stroke patients [33]. As for ANGPT2 rs3020221, it is an sSNP in exon 4 with potential phenotypic consequences and, similarly to our findings, the C allele was associated with poor OS in hepatocellular carcinoma in the single published study [34]. It is, therefore, likely that these ANGPT2 and TEK variants, by altering the expression levels and/or protein activity, may modulate vascular network development, structure, and function, thereby affecting disease progression and patient survival.…”

The role of PNI to predict survival in advanced hepatocellular carcinoma treated with Sorafenib

“…In addition, the pattern of progression [21] and the reason for Sorafenib discontinuation [22] have been reported to have a significant correlation with survival. Furthermore, biological parameters, as serum and plasma proteins [23], genetic markers [24][25][26], micro-RNAs [27], and tissue biomarkers [28] have been investigated. At the moment other potential new biomarkers are under exploration, as the so-called OMICS revolution, Radiomics, and Liquid Biopsy [29].None, of these factors has been validated [30] and they are not usually used in clinical practice to select patients in making clinical decisions.…”

Mitochondrial metabolic study guided by proteomics analysis in hepatocellular carcinoma cells surviving long-term incubation with the highest dose of sorafenib

“…Sorafenib is the first targeted drug approved by the FDA for use in HCC in 2007 and today, sorafenib is still recommended as the standard first-line systemic therapy for HCC patients with advanced disease according to the US National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines [5]. Even though treatment of advanced HCC with sorafenib prolongs median overall survival by 2-3 months [7,8], the clinical outcome is far from satisfactory. AGING…”