Vascular Endothelial Growth Factor Single Nucleotide Polymorphisms Research Articles

VEGFA gene variants are associated with breast cancer progression.

Angiogenesis is recognized as a hallmark of cancer, and vascular endothelial growth factor (VEGF) is a key regulator of the angiogenic process and is related to cancer progression. Anti-VEGF therapy has been tried but with limited success and without useful stratification for angiogenesis markers. Further, the landscape of VEGF single nucleotide polymorphisms (SNPs) in breast cancer and their clinical relevance is not well studied, and their relation to tissue-based angiogenesis markers has not been explored. Here, we studied a selection of VEGFA SNPs in nontumor lymph nodes from a population-based breast cancer cohort (n = 544), and their relation to clinicopathologic variables, vascular tissue metrics, and breast cancer-specific survival. Two of the SNP candidates (rs833068GA genotype and rs25648CC genotype) showed associations with angiogenesis tissue markers, and the VEGFA rs833068GA genotype was associated with breast cancer-specific survival among ER-negative cases. We also found trends of association between the rs699947CA genotype and large tumor diameter and ER-negative tumors, and between the rs3025039CC genotype and large tumor diameter. Our findings indicate some associations between certain VEGF SNPs, in particular the rs833068GA genotype, and both vascular metrics and patient survival. These findings and their potential implications need to be validated by independent studies.

The Relationship between VEGF and AGT Gene Single Nucleotide Polymorphisms and Susceptibility to Renal and Bladder Cancers.

We aimed to examine the relationships between the angiotensinogen (AGT) and vascular endothelial growth factor (VEGF) gene single nucleotide polymorphisms and susceptibility to bladder and kidney cancers. A 1:1 paired case-control study was conducted, which included 143 newly diagnosed kidney cancer cases, 182 newly diagnosed bladder cancer cases, and healthy subjects in the same period collected from two hospitals. Medical records and a questionnaire were used to obtain relevant information. Genotypes were determined by improved multiple ligase detection reaction (iMLDR) and VEGF serum expression levels were detected by enzyme-linked immunosorbent assays (ELISAs). The VEGF gene/genotype frequencies of rs833061 and rs1570360 were statistically different among various pathological grades of kidney cancer, while the AGT rs699 gene/genotype frequencies were statistically different among various pathological types of bladder cancer. In kidney cancer, rs699 was associated with smoking, drinking, and hair coloring, while in bladder cancer, rs699, rs1570360, rs3025039, and rs833061 were associated with smoking, drinking, hair coloring, exercise, and urine holding. This work will help identify biomarkers that can predict the early metastasis and recurrence of kidney or bladder cancer, as well as help improve patient survival rates by predicting their susceptibility. This work will provide reference for the prevention and treatment of kidney and bladder cancers.

ASSOCIATION BETWEEN VASCULAR ENDOTHELIAL GROWTH FACTOR GENE POLYMORPHISMS AND THE RISK OF PREECLAMPSIA IN IRAQI PREGNANT WOMEN

Background: Vascular endothelial growth factor (VEGF) is an essential factor for angiogenesis and plays important role in placental development. Objective: To investigate the association between VEGF single nucleotide polymorphisms (SNPs) +936 Cytosine/Thymine (C/T) and -634 Guanine/Cytosine (G/C) and preeclampsia risk. Methods: A total of 50 cases of pregnant women with preeclampsia and 50 healthy pregnant women (as a control) were involved in this case control study. Blood samples were collected form each woman and the Deoxyribonucleic acid (DNA) was extracted. Amplification of VEGF gene was done by conventional polymerase chain reaction (PCR) and then detection of SNPs-634 G/C and +936 C/T were carried out by restriction fragment length polymorphism PCR (PCR-RFLP). Results: The frequency of different genotypes of VEGF SNPs +936 C/T &-634 G/C are in accordance with Hardy Weinberg equilibrium. VEGF polymorphism +936 C/T appeared in 3 genotypes after digestion with restriction enzymes Cytosine Cytosine (CC), Cytosine Thymine (C/T) & Thymine Thymine (TT). VEGF SNP -634 G/C appeared in 3 genotypes after digestion with restriction enzymes; those were Guanine Guanine (GG), Guanine Cytosine (GC) and CC. The heterozygous genotype CT of polymorphism +936 C/T was more frequent among preeclamptic patients than the controls (26% versus 16%). Likewise, TT genotype was more frequent among preeclamptic patients (8% versus 2%) with no significant differences. At the allelic level, the difference was more prominent. The frequency of mutant allele (T allele) was much more frequent in preeclamptic patients than controls (21% versus 10%) with a statistically significant difference (p=0.049). Although CC genotype of polymorphism -634 G/C was more frequent among preeclamptic patients than controls (14% versus 10%), the difference was not significant (p=0.704). Likewise, there were no significant differences in allele frequency. Conclusion: The study suggested that the mutant T allele of VEGF +936 C/T polymorphism was associated with increased preeclampsia risk and disease development. Keywords: Vascular endothelial growth factor, polymorphisms, preeclampsia Citation: Khaleel MF, Al-Moayad HA. Association between vascular endothelial growth factor gene polymorphisms and the risk of preeclampsia in Iraqi pregnant women. Iraqi JMS. 2022; 20(1): 106-112. doi: 10.22578/IJMS.20.1.14

Biomarkers Associated with Regorafenib First-Line Treatment Benefits in Metastatic Colorectal Cancer Patients: REFRAME Molecular Study.

Simple SummaryBiomarkers able to predict response and toxicity upon regorafenib therapy for colorectal cancer (CRC) are critical for treatment choice, particularly relevant in fragile patients. Here, we validated for the first time 18 distinct microRNAs (miRNAs) detected in serum and primary tumor samples, three germline single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) genes, and low levels of Notch 1 expression in the primary tumor as predictive biomarkers of different features. Specifically, these markers were associated with a favorable response to treatment, disease stage, and relapse, as well as the appearance of asthenia. Therefore, these markers can be potentially useful biomarkers for patient stratification and for providing a more personalized and effective therapeutic strategy in fragile patients, while limiting the appearance of adverse effects.First-line treatment with regorafenib in frail metastatic colorectal cancer (mCRC) patients has shown some benefit. To accurately identify such patients before treatment, we studied blood biomarkers and primary tumor molecules. We unveiled serum microRNAs (miRNAs), single-nucleotide polymorphisms (SNPs) in angiogenic-related genes, and Notch 1 expression as biomarkers associated with response or toxicity. MicroRNA array profiling and genotyping of selected SNPs were performed in the blood of fragile mCRC patients treated with regorafenib. Notch 1 and CRC-associated miRNA expression was also analyzed in tumors. High levels of miR-185-5p in serum, rs7993418 in the vascular endothelial growth factor receptor 1 (VEGFR1) gene, and Notch 1 expression in biopsies were associated with a favorable response to treatment. Serum levels of miR-126-3p and miR-152-3p and tumor expression of miR-92a-1-5p were associated with treatment toxicity, particularly interesting in patients exhibiting comorbidities, and high levels of miR-362-3p were associated with asthenia. Additionally, several miRNAs were associated with the presence of metastasis, local recurrence, and peritoneal metastasis. Besides, miRNAs determined in primary tumors were associated with tumor-node-metastasis (TNM) staging. The rs2305948 and rs699947 SNPs in VEGFR2 and VEGFA, respectively, were markers of poor prognosis correlating with locoregional relapse, a higher N stage, and metastatic shedding. In conclusion, VEGF and VEGFR SNPs, miRNAs, and Notch 1 levels are potential useful biomarkers for the management of advanced CRC under regorafenib treatment.

Association between VEGF single nucleotide polymorphism and breast cancer in the Northern China Han population.

To investigate the associations of four commonly studied single nucleotide polymorphisms (SNP) of the vascular endothelial growth factor (VEGF), including -460T/C (rs833061), - 634G/C (rs2010963), - 2578C/A (rs699947), and +936T/C (rs3025039), with the incidence, aggressiveness, and tumor markers expression of breast cancer in the Northern China Han population. Followed the genomic DNA extraction, a total of 259 patients with breast cancer (case group) and 273 healthy women (control group) underwent genotyping by PCR-LDR SNP assays. The associations between VEGF gene polymorphisms and the incidence, aggressiveness, and tumor markers expression of breast cancer were analyzed. Significant differences were observed in allele frequency and genotype distribution of - 634G/C between breast cancer cases and healthy controls (p = 0.006, 0.013). Individuals who carry the G allele more likely had a lower risk of breast cancer (OR, 0.866, 95% CI 0.782-0.959). Compared with CC genotype carriers, women who had the CG and GG genotypes demonstrated a relatively lower risk (OR, 0.860, 95% CI 0.757-0.978, p = 0.022; OR, 0.778, 95% CI, 0.656-0.924, p = 0.004, respectively). When we stratified the group of patients according to the status of tumor markers, a significant association of - 634G/C SNP and Ki-67 expression was observed. The CC genotype carriers were more likely to be characterized by high expression of Ki-67 (p = 0.031). Further analysis showed that the - 460T/-634C/-2578C/+936C haplotype was more associated with a higher risk of breast cancer (OR, 1.445, 95% CI 1.123-1.859, p = 0.004), whereas the - 460T/- 634G/- 2578C/+936C one was associated with a lower risk (OR, 0.736, 95% CI 0.563-0.963, p = 0.025). In the present study, we concluded that VEGF gene - 634G/C polymorphism is related to the incidence of breast cancer in the Han population in Northern China and also might be associated with tumor proliferation index Ki-67.

Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis.

The associations between vascular endothelial growth factor (VEGF) gene polymorphisms and risk of type 2 diabetic retinopathy (DR) - proliferative diabetic retinopathy (PDR), and nonproliferative diabetic retinopathy (NPDR) - remain unclear. A systematic search and meta-analysis using odds ratio (OR) with 95% confidence interval (CI) was performed to evaluate the association. Our study concluded 26 studies containing 10 single nucleotide polymorphisms (SNPs). In Asian populations, rs3025039 polymorphism was associated with DR risk, while in overall populations and Caucasians, the DR risk was increased by association with rs2010963. There was a significant association between rs25648 and rs833061 and DR risk in Caucasians. DR risks were found to be significantly associated between rs3025021, rs13207351, and rs2146323 in either overall populations, Caucasians or Asians. Besides, in overall and Asian populations, rs699947 and rs3025039 were associated with PDR risk. rs1570360, rs3025039, and rs833061 played a key role in PDR etiology in Caucasians. rs2010963 was associated with increased risk of PDR in overall populations. A significant association between rs699947, rs3025039, and rs833061 and NPDR risk in overall populations and Asians was found. A significant association was observed between rs2010963 and increased NPDR risk in overall and Caucasian populations. This study provides a new insight into the parthenogenesis of diabetic retinopathy. Targeting VEGF SNPs may be a potential of therapeutic approach for the treatment of DR, PDR, and NPDR.

Vascular Endothelial Growth Factor (VEGF) Polymorphisms and Serum VEGF Levels in Women With Epithelial Ovarian Cancer, Benign Tumors, and Healthy Ovaries.

This study analyzed the relation of 5 single-nucleotide polymorphisms (SNPs) in the VEGF (vascular endothelial growth factor) gene in patients with epithelial ovarian cancer (EOC), compared with patients carrying benign tumors or healthy ovaries. We studied serum VEGF levels and the relation with SNPs and association between VEGF SNPs and haplotypes with progression-free survival (PFS) in patients with cancer. The genotyping of VEGF gene polymorphisms (-2578 C/A, -1154 G/A, -460 T/C, +405 G/C, +936 C/T) was performed in DNA isolated from blood samples of 100 women. The different genotypes were evaluated by quantitative real-time polymerase chain reaction. Vascular endothelial growth factor protein concentration was assessed in serum using solid-phase sandwich enzyme-linked immunosorbent assay. We found statistically significant differences in the distribution of VEGF genotypes among the 3 groups of patients: -2578 C/A between those with EOC and healthy ovary (P = 0.04), -460 T/C between those with EOC and healthy ovary (P = 0.03), and -460 T/C between those with benign tumors and healthy ovary (P = 0.02). Vascular endothelial growth factor serum levels were analyzed in patients with EOC. Higher levels were found in patients with clear cell carcinoma compared with those with serous, mucinous, or endometrioid tumors (P < 0.05). No clear association was observed between VEGF SNPs and serum VEGF levels. There was no significant correlation between VEGF SNPs and PFS. In haplotype analysis, CGTCT and CGTGT showed worse prognosis without reaching the statistical significance. CGCGC and AGTGC haplotypes had statistically significant differences among patients with EOC, benign tumors, and healthy ovaries (Ps = 0.046 and 0.041, respectively). The distribution of VEGF genotypes was different in patients with EOC, compared with those with benign tumors or women with healthy ovaries. Vascular endothelial growth factor serum levels were higher in patients with clear cell carcinoma. No correlation was found with improved PFS, but CGTCT and CGTGT haplotypes showed worse prognosis.

Single-nucleotide polymorphisms and haplotypes of vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is one of the most predominant mediators of angiogenesis, plays a critical role in lung carcinogenesis. We performed a case–control study of 209 non-small cell lung cancer (NSCLC) patients and 189 sex, age and smoking matched healthy controls; genotyped 9 VEGF single-nucleotide polymorphisms (SNPs) in patients and controls selected from Kashmiri population and evaluated the NSCLC risk conferred by individual SNPs and haplotypes. In single-locus analysis, alleles of rs699947, rs833061, rs13207351, rs2010963 and rs3025021 showed association with NSCLC [P value=6.00e−04, 2.54e−11, 6.38e−09, 0.0082 and 0.0024]. However permutation test revealed association of only three markers (rs83306, rs13207351 and rs699947) with NSCLC [P value=0.000e0, 0.000e0 and 0.0086], Haplotype analysis of case-control subjects identified one block of two SNPs (rs3025020 and rs3025021) having linkage disequilibrium [D′=0.26]; NSCLC subjects formed two blocks of four SNPs in promoter, 5′-un-translated and intronic region (rs2010963, rs833061, rs13207351 and rs1413711) and four polymorphisms downstream of the coding sequence, in intron and 3′ un-translated region (rs2146323, rs3025020, rs3025021 and rs3025039) with highest linkage disequilibrium [D′=0.89] between rs13207351 and rs3025020. There were no significant differences in the tested single-nucleotide polymorphisms (SNPs) and haplotypes in patients with non-small cell lung cancer.

Promoter polymorphisms of the vascular endothelial growth factor gene are associated with metabolic syndrome susceptibility in Koreans.

Vascular endothelial growth factor (VEGF) is a potent regulator of angiogenesis. Patients with metabolic syndrome (MetS) have elevated plasma VEGF levels. The aim of the present study was to investigate the association between promoter polymorphisms (the -2578C>A and -1154G>A) of the VEGF gene and MetS susceptibility. A total of 640 subjects were enrolled in the study including 320 patients with MetS and 320 healthy controls. Genotyping of the VEGF single nucleotide polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. The CA and AA genotypes of the -2578C>A polymorphism were associated with decreased risk of MetS (P=0.018, P=0.003, respectively). For the -1154G>A polymorphism, although the GA genotype was more significantly frequent in MetS patients (P=0.022), the AA genotype and recessive model (GG+GA vs. AA) were protective against MetS susceptibility (P=0.016, 0.007, respectively). The A-G haplotype frequency composed of the -2578C>A and -1154G>A polymorphisms also differed between the 2 groups (P=0.011). The presented data suggested that the A alleles and A-G haplotype of the VEGF -2578C>A and -1154G>A polymorphisms are associated with decreased MetS susceptibility. To the best of the authors' knowledge, the current study is the first to investigate the associations between the VEGF -2578C>A and -1154G>A polymorphisms and MetS patients. Further evaluation is necessary to explore the associations between the VEGF polymorphisms and MetS patients in larger samples of other ethnic or racial populations.

The Role of Vascular Endothelial Growth Factor Gene Polymorphisms in Recurrent Spontaneous Abortions in Saudi Women

Vascular endothelial growth factor (VEGF) genes regulate proliferation of vascular endothelial cells, hence, are essential for both physiological and pathological angiogenesis. The aim of the present study was to examine the association between three common VEGF single nucleotide polymorphisms (-583 T/C, -1154 G/A, and 936 C/T) and the risk of RSA in Saudi women. A total of 200 women; 100 with RSA-patient matched with 100 controls were enrolled sequentially. Genotyping was conducted using TaqMan assay in order to detect single nucleotide polymorphism (SNPs) in DNA extracts from blood samples. Results showed that the +936C/T allele of VEGF gene is not associated with increased risk of RSA. On the other hand, polymorphisms within -583T/C and -1154G/A of the promotor region were significantly associated with increased RSA risk. Based on these it can be concluded that polymorphisms of VEGF are associated with increased risk of RSA in Saudi women. Hence VEGF gene polymorphism can be a useful biomarker to predict susceptibility to RSA.

Association between the vascular endothelial growth factor single nucleotide polymorphisms and diabetic retinopathy risk: A meta‐analysis

The aim of the present study was to reveal the relationship between vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) and susceptibility to diabetic retinopathy (DR). A literature review was conducted (PubMed, Web of Science, Embase) to identify papers about VEGF SNPs and DR published up to 23 September 2015. The VEGF gene SNPs analyzed with regard to DR susceptibility were rs2010963 (G > C), rs833061 (T > C), rs699947 (C > A), rs3025039 (C > T) and rs1570360 (G > A). Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated, and meta-analyses were performed using fixed or random effects models. Sixteen studies were included in the meta-analysis. Significant associations between the rs3025039 (C > T) polymorphism and increased DR risk were found in the allele model (T/C; pooled OR 1.60, 95% CI 1.07-2.41, P = 0.02), homozygote model (TT/CC; pooled OR 2.08, 95% CI 1.29-3.35, P = 0.003), heterozygote model (TC/CC; pooled OR 1.68, 95% CI 1.04-2.72, P = 0.04), dominant model (TT+TC/CC; pooled OR 1.72, 95% CI 1.06-2.80, P = 0.03), and recessive model (TT/TC+CC; pooled OR 1.80, 95% CI 1.12-2.90, P = 0.02). For rs833061, a significant association between VEGF SNPs and DR was found only in the allele model (C/T; pooled OR 6.34, 95% CI 2.10-19.14, P = 0.001). The rs3025039 and rs833061 SNPs are most likely associated with an increased risk of DR. The T allele in rs3025039 and the C allele in rs833061 are associated with increased DR susceptibility.

VEGF-A and VEGFR1 SNPs associate with preeclampsia in a Philippine population

ABSTRACTThe vascular endothelial growth factor (VEGF) family is important for establishing normal pregnancy, and related single nucleotide polymorphisms (SNPs) are implicated in abnormal placentation and preeclampsia. We evaluated the association between preeclampsia and several VEGF SNPs among Filipinos, an ethnically distinct group with high prevalence of preeclampsia. The genotypes and allelic variants were determined in a case–control study (191 controls and 165 preeclampsia patients) through SNP analysis of VEGF-A (rs2010963, rs3025039) and VEGF-C (rs7664413) and their corresponding receptors VEGFR1 (rs722503, rs12584067, rs7335588) and VEGFR3 (rs307826) from venous blood DNA. VEGF-A rs3025039 C allele has been shown to associate with preeclampsia (odds ratio of 1.648 (1.03–2.62)), while the T allele bestowed an additive effect for the maintenance of normal, uncomplicated pregnancy and against the development of preeclampsia (odds ratio of 0.62 (0.39–0.98)). VEGFR1 rs722503 is associated with preeclampsia occurring at or after the age of 40 years. The results showed that genetic variability of VEGF-A and VEGFR1 are important in the etiology of preeclampsia among Filipinos.

Association of VEGF gene polymorphisms with sporadic Parkinson's disease in Chinese Han population.

Recent evidence indicates that vascular endothelial growth factor (VEGF) is capable of protecting dopaminergic (DA) neurons. Parkinson's disease (PD) is a progressive neurodegenerative disease caused by the degeneration of nigrostriatal dopaminergic neurons. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs) and haplotypes in PD, we performed a case-control study including 400 PD patients and 400 healthy-matched controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis and DNA sequencing were used to detect the rs699947, rs2010963 and rs3025039 polymorphisms of the VEGF gene in cases and controls. Our study revealed that T allelic frequency of rs3025039 polymorphism was significantly higher in PD subjects (OR 1.497, 95% CI 1.099-2.040, P=0.013) than that in controls. Significant association for rs3025039 could be found in additive model (TT vs. CT vs. CC: OR 1.489, 95% CI 1.018-2.177, P=0.040) and dominant model (TT+CT vs. CC: OR 1.538, 95% CI 1.068-2.216, P=0.021). Subgroup analyses performed by gender suggested that this association could be found in male, but not in female. Moreover, it also demonstrated a significant association in the subgroup of late-onset PD (LOPD). However, for rs699947 and rs2010963 polymorphisms, genotype or allele frequencies did not differ between groups. No significant association could be found between rs699947 and rs2010963 polymorphism and PD risk. None of the observed haplotypes showed significant association with PD. Therefore, these results suggested that the VEGF gene might be associated with risk of developing sporadic PD in Han Chinese and the rs3025039 polymorphism may be a risk factor for sporadic PD.

The role of vascular endothelial growth factor −634 G/C and its soluble receptor on chronic liver disease and hepatocellular carcinoma

Background and study aimsThe single nucleotide polymorphism (SNP) of the vascular endothelial growth factor (VEGF) gene −634 G/C (rs2010963) influences the progression of hepatocellular carcinoma (HCC). There have been no studies on the role of VEGF SNP −634 G/C in chronic liver disease (CLD). The aim of the present study was to analyse the correlation between VEGF SNP −634 and the clinical severity of CLD and HCC. Patients and methodsA cross sectional study was conducted on 182 subjects (46 HCC, 39 liver cirrhotic/LC, 38 chronic hepatitis/CH; and 57 healthy subjects). The study was conducted from 2010 to 2014 at the Dr. Sardjito Hospital Yogyakarta, Indonesia. All subjects submitted blood serum for DNA sequencing examination using primer. The clinical data of CLD and HCC were assessed, and sVEGFR-2 was examined in 149 subjects. All data were analysed using STATA programme 11.0. ResultsSignificant differences were observed in genotypic frequency (GG/GC/CC) between HCC, LC, CH and healthy subjects (p=0.004), but though no significant differences were observed between the G>G and C>G genotypic frequencies (p=0.337). The frequency of genotype GG was significantly higher than genotype GC or CC in HCC and was associated with declining of clinical conditions (p<0.05). No significant difference in the distribution genotypes was observed with respect to the level of sVEGFR-2 in the serum. However, we observed a significant correlation between sVEGFR-2 and clinical characteristics in LC and CH (p<0.05). ConclusionGenotype GG of the VEGF SNP −634 is the dominant genotype in severe CLD and HCC. sVEGFR-2 correlates with the disease severity but is not directly associated with the SNP −634 genotype.

Genetic variation in vascular endothelial growth factor gene and its association with recurrent spontaneous abortion.

Vascular endothelial growth factor (VEGF) plays a main role in fetal and placental angiogenesis and is secreted by different cells of endometrium and placenta. In the present study we investigated the association of VEGF gene polymorphisms with recurrent spontaneous abortion (RSA). A case-control study of 100 women with at least two consecutive pregnancy losses before 20 weeks of gestational age and 100 fertile controls was performed to evaluate four VEGF gene polymorphisms including +936C/T (rs3025039), -154G>A (rs1570360), rs3025010 and +5092A/C (rs2146323). Genotyping was performed by PCR based restriction fragment length polymorphism (PCR-RFLP) analysis. Haplotype frequency was estimated for three SNPs' genotypes. Analysis of genetic STRUCTURE and K means clustering were performed to estimate genetic variation. We found an association between -154G/A heterozygous genotype (GA) and RSA. The VEGF single nucleotide polymorphism (SNP) in intron region (rs3025010) in different inheritance models was also associated with RSA. Linkage disequilibrium analysis revealed that VEGF SNP in intron 5 (rs3025010) was linked to promoter region SNP (rs1570360). Cluster analysis including Neighbor Joining and K-means clustering supported genetic differentiation of women with RSA and controls. Allelic polymorphisms in common VEGF SNPs was associated with RSA samples and haplotypes with at least one minor allele showing an association with RSA pathogenesis (Tab. 8, Fig. 2, Ref. 35).

The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology.

Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56–1.03 in SCC; aHR = 1.33, 95% CI = 0.98–1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58–0.97 in SCC; aHR = 1.26, 95% CI = 1.00–1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology.

Abstract 4253: A vascular endothelial growth factor gene polymorphism predicts malignant potential in intraductal papillary mucinous neoplasm

Abstract Background Intraductal papillary mucinous neoplasms (IPMNs) are well known to be premalignant lesions that sequentially progress from adenoma to carcinoma. Radiological type, size of cystic mass, and the presence of mural nodules are widely accepted as predictive malignant factors; however, its underlying mechanism is still unclear. Angiogenesis plays an important role in the progression and metastasis of various tumor types, and vascular endothelial growth factor (VEGF) is a critical component. In previous studies, at least 30 single-nucleotide polymorphisms (SNP) of the VEGF gene have been reported. VEGF +405G/C SNP (rs2010963) is located within the 5′-untranslated region and may affect transcription factor binding affinity. In contrast, VEGF -460C/T SNP (rs833061) is located in the promoter region and may influence promoter activity. Recent studies reported that serum VEGF levels were significantly higher in pancreatic ductal adenocarcinoma (PDAC) patients compared with control subjects, and VEGF +405G/C SNP was strongly associated with the carcinogenesis of PDAC patients. Objective The aim of this study was to investigate the distribution of VEGF SNPs with regard to malignant transformation in IPMN patients. Furthermore, correlations between VEGF SNPs and clinicopathological parameters including the morphological subtypes were statistically analyzed. Methods A total of 169 IPMN and 108 PDAC patients who underwent curative resection were enrolled. Low grade and moderate dysplasia were defined as benign IPMNs, on the other hand, high grade dysplasia and invasive carcinoma were defined as malignant IPMNs. The intraductal components were classified into four distinct epithelial subtypes, gastric, intestinal, pancreatobiliary, and oncocytic, based on their epithelial morphology on hematoxylin and eosin staining. VEGF +405G/C and -460C/T polymorphisms were examined by TaqMan Allele Discrimination. Results VEGF +405C/C was found more frequently in malignant IPMNs compared with +405G/G (odds ratio: 2.7, P = 0.04), and +405C allele was associated with malignant IPMNs compared with +405G (P = 0.055). In branch duct IPMNs, VEGF +405C/C was significantly associated with malignant transformation (CC vs GG; odds ratio: 4.0, P = 0.03, CC vs CG+GG; odds ratio: 3.3, P = 0.04), and there was a trend of VEGF +405C/C associated with malignant transformation of gastric type IPMNs (CC vs GG; odds ratio: 3.0, P = 0.07). When the survival outcomes were analyzed based on VEGF +405G/C SNPs, however, there was no relationship between VEGF SNPs and overall survival in patients with both IPMNs and PDAC. Conclusion VEGF +405G/C SNP was significantly associated with malignant transformation in IPMNs, especially branch duct and gastric type IPMNs. VEGF +405G/C SNP might be helpful in predicting clinical course in pancreatic disease with potential for malignant transformation. Citation Format: Suguru Yamada, Norimitsu Yabusaki, Tsutomu Fujii, Mitsuro Kanda, Hiroyuki Sugimoto, Yasuhiro Kodera. A vascular endothelial growth factor gene polymorphism predicts malignant potential in intraductal papillary mucinous neoplasm. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4253. doi:10.1158/1538-7445.AM2015-4253

Genetic association between VEGF polymorphisms and BRONJ in the Korean population.

The purpose of this study was to evaluate the association between vascular endothelial growth factor (VEGF) polymorphisms and bisphosphonate-related osteonecrosis of the jaw (BRONJ) in the Korean population. Forty-five individuals (2 men, 43 women; mean age: 68.7 ± 12.3 years) were recruited for this study. All visited the Yonsei University Dental Hospital for surgical intervention from January 2012 to January 2013 and had a history of bisphosphonate (BP) administration (oral and/or intravenous). Patients were allocated to case (n = 26) or control (n = 19) groups according to the patients' selection criteria. Association between three VEGF single nucleotide polymorphisms (rs699947 (-2578 C>A), rs2010963 (-634 G>C) and rs3025039 (+936 C>T)) and BRONJ were investigated using multiple logistic regression analysis and Fisher's exact test where appropriate (α = 0.05). The CC homozygotes of rs2010963 and rs3025039 of VEGF gene were associated with an increased risk of BRONJ (P = 0.04, 0.03, respectively). In haplotype analysis, no differences in haplotype C-C (-2578/-634) and haplotype C-C-C (-2578/-634/+936) were observed. The CC homozygotes of rs2010963 and rs3025039 polymorphisms in the VEGF gene were associated with an increased risk of BRONJ in the Korean population. Further epidemiological cohort studies with a larger sample size would be required to confirm the suggestive correlations.

Role of NF-κB activation and VEGF gene polymorphisms in VEGF up regulation in non-proliferative and proliferative diabetic retinopathy.

The present study was aimed to investigate the relation between nuclear factor kappa beta (NFκB) activation and downstream up-regulation of vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR). Moreover the study was intended to evaluate the role of VEGF gene single nucleotide polymorphisms (SNPs) in DR occurrence and to investigate the functional relevance of VEGF gene SNPs in terms of VEGF expression in DR. Serum level of VEGF, VEGF R1 (receptor 1), VEGF R 2 (receptor 2) and NFκB (p50/65) activity was measured by enzyme linked immune sorbent assay. Genotyping and allelic composition of different SNPs i.e., rs2010963, rs3025039, rs1570360 and rs 2071559 were investigated by Taqman SNP genotyping assay. VEGF, NFκB p50/p65, and VEGF R1 & R2 gene expressions were quantified by real time quantitative polymerase chain reaction. Increased NFκB p50/p65 activity and expressions were observed in non proliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) subjects compared to type 2 diabetes mellitus without retinopathy (DNR) group. Significantly elevated levels of serum VEGF and highest VEGF expression were found among PDR subjects compared to DNR or NPDR subjects. CC genotype and C allele of rs2010963 and TT genotype and T allele of rs3025039 were significantly over represented among PDR subjects compared to DNR group. Increased activation of NFκβ in NPDR and PDR subjects might involve increased up regulation of VEGF. VEGF SNPs i.e., rs2010963 C allele and rs3025039 T allele might be associated with PDR occurrence and in turn regulates VEGF expression among PDR subjects.

A vascular endothelial growth factor gene polymorphism predicts malignant potential in intraductal papillary mucinous neoplasm.

The aim of this study was to evaluate the clinical relevance of vascular endothelial growth factor (VEGF) single nucleotide polymorphisms (SNPs) in intraductal papillary mucinous neoplasms (IPMNs). A total of 169 IPMN and 108 pancreatic ductal adenocarcinoma patients who underwent curative resection were enrolled, and VEGF +405G/C and -460C/T SNPs were investigated. Vascular endothelial growth factor +405C/C was found more frequently in malignant IPMNs compared with +405G/G (odds ratio [OR], 2.7; P = 0.04), and +405C allele was associated with malignant IPMNs compared with +405G (P = 0.055). In branch duct IPMNs, VEGF +405C/C was significantly associated with malignant transformation (CC vs GG: OR, 4.0; P = 0.03; CC vs CG + GG: OR, 3.3; P = 0.04), and there was a trend of VEGF +405C/C associated with malignant transformation of gastric-type IPMNs (CC vs GG: OR, 3.0; P = 0.07). When the survival outcomes were analyzed based on VEGF +405G/C SNPs, however, there was no relationship between VEGF SNPs and overall survival in patients with both IPMNs and pancreatic ductal adenocarcinomas. Vascular endothelial growth factor +405G/C SNP was significantly associated with malignant transformation in IPMNs, especially branch duct and gastric-type IPMNs. Vascular endothelial growth factor +405G/C SNP might be helpful in predicting clinical course in pancreatic disease with potential for malignant transformation.