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NRP-1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer.

ABSTRACT: Neuropilin-1 (NRP-1), a member of the NRP-family, has been reported to be vital for tumor angiogenesis, growth and metastasis. As a co-receptor of vascular endothelial growth factor (VEGF), NRP-1 can bind to VEGF and meditate vascular development through the VEGF-VEGF receptor 2 (VEGFR2) signaling pathway. Furthermore, NRP-1 is capable of binding with platelet-derived growth factor (PDGF) to regulate the PDGF-PDGF receptor (PDGR) signaling pathway in tumor angiogenesis. In the present study, The DNA was obtained from the paraffin-embedded tissues of patients with advanced gastric cancer (AGC), amplified using PCR and subsequently sequenced to determine the polymorphisms within NRP-1, VEGFR2 [kinase insert domain receptor (KDR)] and PDGF. The effect of the functional polymorphism of the aforementioned genes on the overall survival (OS) and progression-free survival (PFS) of 81 patients with advanced gastric cancer was examined. Three single nucleotide polymorphisms (SNPs) of KDR were significantly associated with clinical outcomes. The rs1870377 TT genotype was positively associated with longer OS and PFS times compared with the AA+AT genotype (PFS, P=0.012; OS, P=0.038), the rs7692791 wild-type TT genotype was positively associated with longer PFS time and the rs2034965 AA+GA genotype was associated with shorter OS time (P=0.034). With regards to the SNPs of NRP-1, the rs2065364 AA genotype was significantly associated with improved OS and PFS times (PFS, P=0.023; OS, P=0.045). Following multivariate analysis using Cox proportional hazards regression models, patients with the KDR rs7692791 TT genotype experienced a longer PFS time compared with those with the CT genotype (P=0.016), and patients with the NRP-1 rs2065364 variant-type AA genotype still experienced a longer PFS time compared with those patients with the AG+GG genotypes (P=0.006). Regarding OS, the results demonstrated that the KDR rs2034965 AG+GG genotypes presented with a significant reduction in OS time (P=0.029), and that the KDR rs1870377 AT+AA genotypes had worse OS times compared with the wild-type TT genotype (P=0.021). In addition, increased mortality risk and AGC progression were significantly associated with the number of adverse alleles for combinations of NRP-1 rs2065364 and KDR rs1870377. In conclusion, the data from the present study demonstrated that the selected KDR and NRP-1 gene polymorphisms may be potential prognostic biomarkers in AGC.

SUBMITTER: Zhuo YJ

PROVIDER: S-EPMC6781724 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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NRP-1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer.

Zhuo Yue-Jian YJ Shi Yu Y Wu Tao T

Oncology letters 20190910 5

Neuropilin-1 (NRP-1), a member of the NRP-family, has been reported to be vital for tumor angiogenesis, growth and metastasis. As a co-receptor of vascular endothelial growth factor (VEGF), NRP-1 can bind to VEGF and meditate vascular development through the VEGF-VEGF receptor 2 (VEGFR2) signaling pathway. Furthermore, NRP-1 is capable of binding with platelet-derived growth factor (PDGF) to regulate the PDGF-PDGF receptor (PDGR) signaling pathway in tumor angiogenesis. In the present study, The ...[more]

PMID: 31611971

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Project description:BackgroundSerum tumor markers including AFU, AFP, CEA, CA199, CA125 and CA724, are of great importance in the diagnosis, prognostic prediction and recurrence monitoring of gastrointestinal malignancies. However, their significance in gastric cancer (GC) patients with neoadjuvant therapy (NCT) is still uncertain. The aim of this study was to evaluate the predictive value of these six tumor markers in locally advanced GC patients who underwent NCT and curative surgery.MethodsIn total, 290 locally advanced GC patients who underwent NCT and D2 radical gastrectomy were retrospectively analyzed. Data on their tumor markers before (pre-) and after (post-) NCT and pathological characteristics were extracted from the database of our hospital. The optimal cutoff values of the six tumor markers were calculated by the ROC curve and Youden index. Their predictive significance was analyzed and survival curves for overall survival (OS) were obtained by the Kaplan-Meier method. Associations between categorical variables were explored by the chi-square test or Fisher's exact test. Multivariate analyses were performed by the Cox regression model.ResultsPre- and post-CA199, -CA125 and -CA724 could predict overall survival (all P < 0.05), but only the change (diff-) of CA199 was related to prognosis (P = 0.05). In the multivariable analysis, pre- (P = 0.014) and post-CA724 (P = 0.036) remained significant, though diff-CA724 was not an independent prognostic factor (P = 0.581). In addition, pre- and post-CA199, -CA125 and -CA724 were associated with lymph node metastasis (N- vs N+) and pathological stage (I-II vs III) (all P < 0.05). Moreover, post-CA724 was related to the vascular or lymphatic invasion (P = 0.019), while pre-CA724 was not (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05).ConclusionsCA724 is an independent factor for prognosis and could be used to predict ypN and ypTNM stage in locally advanced GC patients undergoing NCT and curative resection.

Project description:IntroductionGermline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.MethodsGermline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.ResultsA comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.ConclusionsThis study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.

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NRP-1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer.

Publications

NRP-1 and KDR polymorphisms are associated with survival time in patients with advanced gastric cancer.

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