eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: Final results of the ePHAS study

Andrea Casadei Gardini, Giorgia Marisi, Luca Faloppi, Emanuela Scarpi, Francesco Giuseppe Foschi, Massimo Iavarone, G. Lauletta, J. Corbelli, Martina Valgiusti, Floriana Facchetti, Cristina Della Corte, Luca M. Neri, Stefano Tamberi, Stefano Cascinu, Mario Scartozzi, Dino Amadori, Oriana Nanni, Elena Tenti, Paola Ulivi, Giovanni Luca Paolo Frassineti

Research output: Contribution to journalArticle

Abstract

Sorafenib may reduce endothelial nitric oxide synthase (eNOS) activity by inhibiting vascular endothelial growth factor receptors (VEGF-R), leading to a decrease in nitric oxide production. In the Italian multicenter ePHAS (eNOS polymorphisms in HCC and sorafenib) study, we analyzed the role of eNOS polymorphisms in relation to clinical outcome in patients with hepatocellular carcinoma (HCC) receiving sorafenib. Our retrospective study included a training cohort of 41 HCC patients and a validation cohort of 87 HCC patients, all undergoing sorafenib treatment. Three eNOS polymorphisms (eNOS -786T>C, eNOS VNTR 27bp 4a/b and eNOS+894G>T) were analyzed by direct sequencing or Real Time PCR in relation to progressionfree survival (PFS) and overall survival (OS) (log-rank test). In univariate analysis, training cohort patients homozygous for eNOS haplotype (HT1:T-4b at eNOS-786/eNOS VNTR) had a lower median PFS (2.6 vs. 5.8 months, P <0.0001) and OS (3.2 vs.14.6 months, P = 0.024) than those with other haplotypes. In the validation set, patients homozygous for HT1 had a lower median PFS (2.0 vs. 6.7 months, P <0.0001) and OS (6.4 vs.18.0 months, P <0.0001) than those with other haplotypes. Multivariate analysis confirmed this haplotype as the only independent prognostic factor. Our results suggest that haplotype HT1 in the eNOS gene may be capable of identifying a subset of HCC patients who are resistant to sorafenib.

Original languageEnglish
Pages (from-to)27988-27999
Number of pages12
JournalOncotarget
Volume7
Issue number19
DOIs
Publication statusPublished - May 10 2016

Fingerprint

Nitric Oxide Synthase Type III
Hepatocellular Carcinoma
Haplotypes
Survival
sorafenib
Vascular Endothelial Growth Factor Receptor
Real-Time Polymerase Chain Reaction
Nitric Oxide
Multivariate Analysis
Retrospective Studies

Keywords

  • Angiogenesis
  • Biomarkers
  • Endothelial nitric oxide synthase
  • Hepatocellular carcinoma
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Oncology

Cite this

eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib : Final results of the ePHAS study. / Casadei Gardini, Andrea; Marisi, Giorgia; Faloppi, Luca; Scarpi, Emanuela; Foschi, Francesco Giuseppe; Iavarone, Massimo; Lauletta, G.; Corbelli, J.; Valgiusti, Martina; Facchetti, Floriana; Della Corte, Cristina; Neri, Luca M.; Tamberi, Stefano; Cascinu, Stefano; Scartozzi, Mario; Amadori, Dino; Nanni, Oriana; Tenti, Elena; Ulivi, Paola; Frassineti, Giovanni Luca Paolo.

In: Oncotarget, Vol. 7, No. 19, 10.05.2016, p. 27988-27999.

Research output: Contribution to journalArticle

Casadei Gardini, A, Marisi, G, Faloppi, L, Scarpi, E, Foschi, FG, Iavarone, M, Lauletta, G, Corbelli, J, Valgiusti, M, Facchetti, F, Della Corte, C, Neri, LM, Tamberi, S, Cascinu, S, Scartozzi, M, Amadori, D, Nanni, O, Tenti, E, Ulivi, P & Frassineti, GLP 2016, 'eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib: Final results of the ePHAS study', Oncotarget, vol. 7, no. 19, pp. 27988-27999. https://doi.org/10.18632/oncotarget.8569
Casadei Gardini, Andrea ; Marisi, Giorgia ; Faloppi, Luca ; Scarpi, Emanuela ; Foschi, Francesco Giuseppe ; Iavarone, Massimo ; Lauletta, G. ; Corbelli, J. ; Valgiusti, Martina ; Facchetti, Floriana ; Della Corte, Cristina ; Neri, Luca M. ; Tamberi, Stefano ; Cascinu, Stefano ; Scartozzi, Mario ; Amadori, Dino ; Nanni, Oriana ; Tenti, Elena ; Ulivi, Paola ; Frassineti, Giovanni Luca Paolo. / eNOS polymorphisms and clinical outcome in advanced HCC patients receiving sorafenib : Final results of the ePHAS study. In: Oncotarget. 2016 ; Vol. 7, No. 19. pp. 27988-27999.
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