Genetic interaction analysis of VEGF-A rs3025039 and VEGFR-2 rs2071559 identifies a genetic profile at higher risk to develop nodular goiter.

CONTEXT: Nodular goiter in patients from areas of iodine deficiency is due to the growth of follicular and endothelial cells, involving different vascular-related growth factors in its pathogenesis. OBJECTIVE: The aim of our study was to examine the association of known single polymorphisms of vascular endothelial growth factor-A [VEGF-A], VEGF receptor-2 [VEGFR-2] and hypoxia-inducible factor-1α [HIF-1α] genes or their genetic interactions with the risk of nodular goiter development. PATIENTS AND METHODS: 116 normal subjects, without any thyroid disease, and 108 subjects with nodular goiter [subjects with goiter and at least one thyroid nodule of > 1 cm of maximum size and in absence of signs of autoimmunity] were selected from a homogeneous population living in a mild iodine deficiency geographic area. Analyses were performed on germline DNA obtained from blood samples and VEGF-A rs3025039, VEGFR-2 rs2071559, and HIF-1αrs11549465 SNPs were investigated by real-time PCR technique. The multifactor dimensionality reduction [MDR] methodology was applied to investigate the genetic interaction between SNPs. Hardy-Weinberg equilibrium was performed. RESULTS: None of the studied polymorphisms were individually associated with a higher risk to develop nodular goiter [P > 0.05]. The combination of the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms had the highest accuracy of 0.58 [P = 0.018] and the interaction of some genotypes was significantly associated with the risk of nodular goiter development. CONCLUSIONS: Our results support a genetic interaction between the VEGF-A rs3025039 and VEGFR-2 rs2071559 polymorphisms as a predictor of the risk to develop nodular goiter in subjects coming from an area with mild iodine deficiency.

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide.

BACKGROUND: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. METHODS: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (-2578A/C, -634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy-Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan-Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant. RESULTS: Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the -2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the -634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the -634CC genotype had a median PFS of 2.2 months whereas patients with the genotype -634CG/GG had a median PFS of 6.25 months (P=0.0042). CONCLUSION: The -634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule.

Pharmacodynamic and pharmacogenetic angiogenesis-related markers of first-line FOLFOXIRI plus bevacizumab schedule in metastatic colorectal cancer.

BACKGROUND: The identification of molecular and genetic markers to predict or monitor the efficacy of bevacizumab (BV) represents a key issue in the treatment of metastatic colorectal cancer (mCRC). METHODS: Plasma levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble VEGF receptor 2 (sVEGFR-2) and thrombospondin-1 (TSP-1) were assessed by ELISA assay at different time points in a cohort of 25 patients enroled in a phase II trial of GONO-FOLFOXIRI plus BV as first-line treatment of mCRC. VEGF: -2578A/C, -1498C/T, -1154A/G, -634C/G and 936C/T; and VEGFR-2: -604A/G, +1192C/T and +1719A/T, polymorphisms were assessed in a total of 54 patients. RESULTS: Treatment with GONO-FOLFOXIRI plus BV determined a prolonged and significant reduction in plasma free, biologically active VEGF concentration. Interestingly, VEGF concentrations remained lower than at baseline also at the time of PD. Conversely, PlGF levels increased during the treatment if compared with baseline, suggesting a possible role in tumour resistance; moreover, sVEGFR-2 increased at the time of PD, as well as TSP-1. No association of assessed polymorphisms with outcome was found. CONCLUSION: Our study suggested the possible mechanisms of resistance to combined therapy in those patients with a progressive disease to be tested in ongoing phase III randomised studies.