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Open AccessArticle

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

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Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
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Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
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CellNetworks—Cluster of Excellence (EXC81) and Biochemistry Center (BZH), Heidelberg University, 69120 Heidelberg, Germany
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Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, 20141 Milan, Italy
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Department of Medical Oncology, University Hospital Cagliari, 09124 Cagliari, Italy
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DPT Internal Medicine, Faenza Hospital, AUSL Romagna, 48018 Faenza, Italy
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Department of Biomedical Sciences and Human Oncology, Internal Medicine “G. Baccelli”, University of Bari “A. Moro”, 70121 Bari, Italy
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“A.M.&A. Migliavacca” Center for Liver Disease, 1st Division of Gastroenterology, Fondazione IRCCS Ca’ Granda Maggiore Hospital, University of Milan, 20122 Milan, Italy
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Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy
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Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy
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Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, 41121 Modena, Italy
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Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy
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General and Oncology Surgery, Morgagni-Pierantoni Hospital, 47121 Forli, Italy
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Department of Medical & Surgical Sciences—DIMEC, Alma Mater Studiorum—University of Bologna, 40138 Bologna, Italy
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2019, 11(7), 1023; https://doi.org/10.3390/cancers11071023
Received: 1 July 2019 / Revised: 16 July 2019 / Accepted: 17 July 2019 / Published: 20 July 2019
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. View Full-Text
Keywords: single-nucleotide polymorphism; angiopoietin; endothelial nitric oxide synthase; hepatocellular carcinoma; biomarkers; angiogenesis; Child–Pugh; VEGF single-nucleotide polymorphism; angiopoietin; endothelial nitric oxide synthase; hepatocellular carcinoma; biomarkers; angiogenesis; Child–Pugh; VEGF
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Marisi, G.; Petracci, E.; Raimondi, F.; Faloppi, L.; Foschi, F.G.; Lauletta, G.; Iavarone, M.; Canale, M.; Valgiusti, M.; Neri, L.M.; Ulivi, P.; Orsi, G.; Rovesti, G.; Vukotic, R.; Conti, F.; Cucchetti, A.; Ercolani, G.; Andrikou, K.; Cascinu, S.; Scartozzi, M.; Casadei-Gardini, A. ANGPT2 and NOS3 Polymorphisms and Clinical Outcome in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib. Cancers 2019, 11, 1023.

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