Clinica di Oncologia Medica, Università Politecnica delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
Chirurgia del Pancreas, Ospedale San Raffaele IRCCS, Università Vita e Salute, Milano, Italy.
PLoS One. 2018 May 22;13(5):e0197035. doi: 10.1371/journal.pone.0197035. eCollection 2018.
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.
血管生成是癌症发展的关键事件，导致局部侵袭和转移，并且可能被认为是具有高血管生成分子表达的胃肠胰神经内分泌肿瘤 (GEP-NENs) 的基本特征。我们旨在通过分析血管内皮生长因子 A (VEGF-A)、血管内皮生长因子受体 2 (VEGFR2) 和血管内皮生长因子受体 3 (VEGFR3) 的单核苷酸多态性 (SNP) 来分析血管生成因子在 GEP-NENs 中的预后和预测作用。从我们机构治疗的 58 例连续 GEP-NEN 患者的外周血中提取基因组 DNA。分别在 VEGF-A(rs2010963G>C，rs699947A>C)、VEGFR-2(rs2305948C>T，rs1870377T>A)和 VEGFR-3(rs307821T>C，rs307826C>A)基因中鉴定出两个 SNP。通过使用 TaqMan 测定法的实时 PCR 确定基因多态性。中位年龄为 57 岁(范围 24-79 岁)；32 名患者为男性，77.5%的 NENs 位于胰腺。VEGFR-2 rs2305948T 和 VEGF-A rs2010963C 的等位基因频率显示出比一般人群更高的频率趋势(分别为 12.1%比 8.0%和 34.5%比 31.2%)。三个 SNP(rs699947C、rs2010963GC 和 rs307821C)与疾病复发风险增加相关。此外，根据存在 0-1 个 SNP(20.7%的病例；61.9 个月)、2 个 SNP(25.9%；49.2 个月)和 3 个 SNP(53.4%；27.8 个月)，中位 PFS 发生变化(p = 0.034)。结果首次表明，VEGF-A 和 VEGFR-3 中的特定 SNP 与 GEP-NENs 的不良预后相关。确定这种新的预后因素可能有助于优化这些异质性肿瘤的治疗。
