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

Giorgia Marisi, Elisabetta Petracci, Francesco Raimondi, Luca Faloppi, Francesco Giuseppe Foschi, Gianfranco Lauletta, Massimo Iavarone, Matteo Canale, Martina Valgiusti, Luca Maria Neri, Paola Ulivi, Giulia Orsi, Giulia Rovesti, Ranka Vukotic, Fabio Conti, Alessandro Cucchetti, Giorgio Ercolani, Kalliopi Andrikou, Stefano Cascinu, Mario Scartozzi, Andrea Casadei-Gardini, Giorgia Marisi, Elisabetta Petracci, Francesco Raimondi, Luca Faloppi, Francesco Giuseppe Foschi, Gianfranco Lauletta, Massimo Iavarone, Matteo Canale, Martina Valgiusti, Luca Maria Neri, Paola Ulivi, Giulia Orsi, Giulia Rovesti, Ranka Vukotic, Fabio Conti, Alessandro Cucchetti, Giorgio Ercolani, Kalliopi Andrikou, Stefano Cascinu, Mario Scartozzi, Andrea Casadei-Gardini

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.

Keywords: Child–Pugh; VEGF; angiogenesis; angiopoietin; biomarkers; endothelial nitric oxide synthase; hepatocellular carcinoma; single-nucleotide polymorphism.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Kaplan–Meier curves for ANGPT2 rs55633437. (a) Progression-free survival (PFS) and (b) overall survival (OS) in relation to ANGPT2 rs55633437 genotypes.
Figure 2
Figure 2
Kaplan–Meier curves for ANGPT2 rs3020221 and rs1961222. OS in relation to rs3020221 genotypes (a) and rs1961222 genotypes (b).
Figure 3
Figure 3
Kaplan–Meier curves for eNOS single-nucleotide polymorphisms (SNPs). (a) Progression-free survival (PFS) and (b) overall survival (OS) in relation to eNOS rs2070744T > C genotypes; (c) PFS in relation to eNOS VNTR4a/b genotypes.
Figure 4
Figure 4
Kaplan–Meier curves for ANGPT2 haplotype 2 (Block 2). (a) Progression-free survival (PFS) and (b) overall survival (OS).

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