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Vascular endothelial growth factor and VEGF -1154 G/A SNP in GEP-NET tumorigenesis

Angiogenesis plays a crucial role in tumour growth and metastasis and vascular endothelial growth factor (VEGF) is one of the most important factors promoting angiogenesis. Increased levels of VEGF influence vascular density, lead to malignant effusions, and therefore correlate with worse prognosis in different types of solid tumours. Recent clinical data suggest that higher levels of VEGF also correlate with tumour radio-, chemo- and hormone therapy resistance. VEGF expression is regulated at the transcriptional level, and there have been many SNPs in the promoter region found to increase VEGF levels. Among them -1154 G/A SNP has also been found to change susceptibility to gastrointestinal cancer. Neuroendocrine tumours of gastrointestinal tract (GI-NET) and pancreas (PET) are rare highly vascularized neoplasms, whose pathogenesis is still largely unknown. VEGF-mediated pathway is one of the most promising target in novel treatment options used for management of these tumours. We investigated correlation between VEGF -1154 G/A SNP and susceptibility to GI-NET and PET development. Correlation between VEGF -1154 genotypes and VEGF serum levels in GEP-NET patients was also investigated, as well as the role of VEGF as a potential new GEP-NET marker (compared to serum chromogranin A-CgA and 5-hydroxyindolacetic acid-5-HIAA in 24-hour urine). The study included 101 patient diagnosed with GEP-NET (55 with GI-NET and 46 with PET). For control group DNAs from 150 healthy age- and sex-matched volunteers was used. As there was no upper limit of normal for the VEGF serum levels, VEGF was also determined in sera of 20 healthy volunteers. The distribution of VEGF -1154 G/A SNP polymorphism was compared between GI-NET and PET patients and controls. For the mentioned analyses odds ratio was used. As VEGF serum levels did not follow normal distribution (tested by Shapiro-Wilks test of normality), for further analysis non-parametric Kruskal-Wallis test was used. Patients’ VEGF serum levels were compared to VEGF -1154 G/A SNP genotypes and finally with known markers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid (5-HIAA). The level of significance was 0.05. There was a statistically significant association between high expression (GG and AG) and GG genotypes and risk of GI-NET development (odds ratio, 3.7644 ; 95% CI, 1.199-11.8192 ; p=0.0173 and 3.0558 ; 95% CI, 1.0219-9.1381 ; p=0.0373, respectively, Table 1A). There was also a statistically significant association between high expression G-allele and risk of GI-NET development (odds ratio, 1.7894 ; 95% CI 1.1173-2.8656 ; p= 0.0147, Table 1A). Both high expression GG genotype and G-allele were more frequent in patients (49.1% vs. 34.67% and 70.9% vs. 57.67%, respectively, Table 1A). When controls were compared with PET patients there was no difference in genotype or allele distribution between patients and controls (Table 1B). VEGF serum levels were elevated in 40.6% of patients, with upper limit of normal set at 270.6 pg/mL (Table 2). VEGF serum levels correlated with G allele, and GG homozygous patients had highest VEGF levels (mean value of VEGF serum level in patients with AA genotype was 127.092 pg/ml and 335.94 pg/ml in GG carriers, p=0.003), also highest VEGF levels were detected in patients with liver metastases (376.3 pg/mL). When compared to standard VEGF markers, sensitivity of VEGF serum levels was better than 5-HIAA (p=0.0006), and inferior to CgA (p=0.06). In case of metastatic GEP-NET disease, besides elevation of CgA and 5-HIAA, patients had elevated VEGF serum levels (p= 0.06, Kruskal-Wallis test). According to our data, VEGF -1154 G/A SNP contributes to GI-NET susceptibility. G-allele of the VEGF -1154 SNP has a functional activity in GEP-NETs, while highest serum VEGF levels were detected in patients homozygous for the mentioned allele. Also, highest values were detected in patients with metastatic disease, and when compared to standard neuroendocrine markers, in those patients VEGF was superior to 5-HIAA. To conclude, VEGF may play an important role in GI-NET development and metastatic potential and in future it may become an important marker in GEP-NET patient follow-up.

VEGF; GEP-NET

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