Impact of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) single nucleotide polymorphisms on outcome in gastroenteropancreatic neuroendocrine neoplasms.

Rossana Berardi,Alberto Murrone,Francesca Bianchi,Federica Barucca,Mariangela Torniai,Vanessa Polenta,Corrado Rubini,Agnese Savini,Matteo Santoni,Riccardo Giampieri,Massimo Falconi,Stefano Partelli,Sofia Onorati,Silvia Pagliaretta,Daotai Nie

doi:10.1371/journal.pone.0197035

Abstract

Angiogenesis represents a key event in cancer development, leading to local invasion e metastatization, and might be considered a basic feature in gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with a high expression of angiogenic molecules. We aimed to analyze the prognostic and predictive role of angiogenic factors in GEP-NENs through the analysis of single nucleotide polymorphisms (SNPs) of VEGF-A, VEGFR2 and VEGFR3. The genomic DNA of 58 consecutive patients with GEP-NENs treated at our Institution was extracted from peripheral blood. Two SNPs were identified respectively in VEGF-A (rs2010963G>C, rs699947A>C), VEGFR-2 (rs2305948C>T, rs1870377T>A), and VEGFR-3 (rs307821T>C, rs307826C>A) gene. Gene polymorphisms were determined by Real-Time PCR using TaqMan assays. Median age was 57 years (range 24–79 years); 32 patients were male and 77.5% of NENs were localized in the pancreas. The allele frequency of VEGFR-2 rs2305948T and of VEGF-A rs2010963C showed a trend of higher frequency than in general population (12.1% vs. 8.0% and 34.5% vs. 31.2%, respectively). Three out SNPs (VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C) showed a correlation with an increased risk of disease relapse. Moreover median PFS changes according to the presence of 0–1 SNPs (20.7% of cases; 61.9 months), 2 SNPs (25.9%; 49.2 months) and 3 SNPs (53.4%; 27.8 months) (p = 0.034). Results suggest, for the first time, that specific SNPs in VEGF-A and VEGFR-3 correlate with poor prognosis in GEP-NENs. The identification of this new prognostic factor might be helpful in order to optimize the management of these heterogeneous neoplasms.

Highlights

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogeneous family of diseases arising from homonym cells distributed in pancreatic islets and in the digestive tract.The incidence of GEP-NENs has substantially increased 3.65-fold in the USA and 3.8 to 4.8-fold in Europe over the past four decades [1], primarily due to a considerable improvement of diagnostic tools. traditionally considered slow progressing tumors, their clinical behaviour might be very aggressive [2] depending on tumor grading, disease staging and primary tumor site [3]
We evaluated the expression of some single nucleotide polymorphisms (SNPs) of Vascular endothelial growth factors (VEGFs)-A, VEGFR-2 and VEGFR-3 focusing on their potential role in neoplasm susceptibly and their prognostic significance
The following SNPs, VEGF-A rs699947C, VEGF-A rs2010963GC and VEGFR-3 rs307821C, significantly correlated with a shorter progression free survival (PFS) suggesting, for the first time, that abnormalities in VEGF pathway might act as prognostic factors in GEP-NENs

Summary

Introduction

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogeneous family of diseases arising from homonym cells distributed in pancreatic islets and in the digestive tract.The incidence of GEP-NENs has substantially increased 3.65-fold in the USA and 3.8 to 4.8-fold in Europe over the past four decades [1], primarily due to a considerable improvement of diagnostic tools. traditionally considered slow progressing tumors, their clinical behaviour might be very aggressive [2] depending on tumor grading, disease staging and primary tumor site [3]. Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogeneous family of diseases arising from homonym cells distributed in pancreatic islets and in the digestive tract. The incidence of GEP-NENs has substantially increased 3.65-fold in the USA and 3.8 to 4.8-fold in Europe over the past four decades [1], primarily due to a considerable improvement of diagnostic tools. Traditionally considered slow progressing tumors, their clinical behaviour might be very aggressive [2] depending on tumor grading, disease staging and primary tumor site [3]. Clinical management of GEP-NENs is still challenging and should be conducted under a multidisciplinary approach. Surgery still remains the only potentially curative therapeutic option, mainly depending on tumor size and patient’s performance status [5]. In locally-advanced and metastatic setting, medical therapy includes somatostatin analogues (SSAs), peptide receptor radionuclide therapy (PRRT), targeted agents as angiogenesis and mTOR (mammalian target of rapamycin) inhibitors and chemotherapy, but the optimal sequence still represents matter of debate [6]

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