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Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer.

ABSTRACT: Angiogenesis plays a key role in the development and treatment response of various tumors. The signaling transductions mediated by the binding of vascular endothelial growth factor (VEGF) to its receptor KDR (kinase insert domain receptor) is the most important pathway in tumor angiogenesis. Single nucleotide polymorphisms (SNPs) in VEGF have been extensively implicated in the etiology and treatment outcome of colorectal cancer (CRC). However, no study has been reported evaluating the role of KDR SNPs in CRC prognosis. We herein assessed the association between four potentially functional KDR SNPs and tumor recurrence in a Chinese population with 408 surgically resected CRC patients. The most significant SNP was for rs10013228 located in the KDR gene promoter. Compared with the homozygous wild-type genotype, the variant-containing genotypes of this SNP were significantly associated with a reduced recurrence risk with a hazard ratio (HR) of 0.53 (95% confidence interval [CI] 0.30-0.95, P = 0.032). Moreover, a borderline significant association was noted for another promoter SNP, rs2071559, with an HR of 0.67 (95% CI 0.42-1.07, P = 0.092). In stratified analysis, the associations of both SNPs were more prominent in patients receiving chemotherapy (HR = 0.47, 95% CI 0.23-0.94, P = 0.033 for rs10013228 and HR = 0.55, 95% CI 0.32-0.95, P = 0.032 for rs2071559). Further analysis revealed a protective effect on patient recurrence by chemotherapy (HR = 0.56, 95% CI 0.32-1.01, P = 0.046), which was more evident in patients with the variant-containing genotypes of each of the two SNPs (HR = 0.09, 95% CI 0.02-0.55, P = 0.009 for rs10013228 and HR = 0.39, 95% CI 0.18-0.86, P = 0.020 for rs2071559). Collectively, our findings suggest SNPs in the KDR gene modulate CRC recurrence, especially in those receiving chemotherapy.

SUBMITTER: Dong G

PROVIDER: S-EPMC7713614 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer.

Dong Guanglong G Guo Xu X Fu Xiaoying X Wan Shaogui S Zhou Feng F Myers Ronald E RE Bao Guoqiang G Burkart Ashlie A Yang Hushan H Xing Jinliang J

Cancer science 20120116 3

Angiogenesis plays a key role in the development and treatment response of various tumors. The signaling transductions mediated by the binding of vascular endothelial growth factor (VEGF) to its receptor KDR (kinase insert domain receptor) is the most important pathway in tumor angiogenesis. Single nucleotide polymorphisms (SNPs) in VEGF have been extensively implicated in the etiology and treatment outcome of colorectal cancer (CRC). However, no study has been reported evaluating the role of KD ...[more]

PMID: 22182247

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Project description:BackgroundColorectal cancer (CRC) is a common malignant solid tumor with an extremely low survival rate after relapse. Previous investigations have shown that autophagy possesses a crucial function in tumors. However, there is no consensus on the value of autophagy-associated genes in predicting the prognosis of CRC patients. This work screens autophagy-related markers and signaling pathways that may participate in the development of CRC, and establishes a prognostic model of CRC based on autophagy-associated genes.MethodsGene transcripts from the TCGA database and autophagy-associated gene data from the GeneCards database were used to obtain expression levels of autophagy-associated genes, followed by Wilcox tests to screen for autophagy-related differentially expressed genes. Then, 11 key autophagy-associated genes were identified through univariate and multivariate Cox proportional hazard regression analysis and used to establish prognostic models. Additionally, immunohistochemical and CRC cell line data were used to evaluate the results of our three autophagy-associated genes EPHB2, NOL3, and SNAI1 in TCGA. Based on the multivariate Cox analysis, risk scores were calculated and used to classify samples into high-risk and low-risk groups. Kaplan-Meier survival analysis, risk profiling, and independent prognosis analysis were carried out. Receiver operating characteristic analysis was performed to estimate the specificity and sensitivity of the prognostic model. Finally, GSEA, GO, and KEGG analysis were performed to identify the relevant signaling pathways.ResultsA total of 301 autophagy-related genes were differentially expressed in CRC. The areas under the 1-year, 3-year, and 5-year receiver operating characteristic curves of the autophagy-based prognostic model for CRC were 0.764, 0.751, and 0.729, respectively. GSEA analysis of the model showed significant enrichment in several tumor-relevant pathways and cellular protective biological processes. The expression of EPHB2, IL-13, MAP2, RPN2, and TRAF5 was correlated with microsatellite instability (MSI), while the expression of IL-13, RPN2, and TRAF5 was related to tumor mutation burden (TMB). GO analysis showed that the 11 target autophagy genes were chiefly enriched in mRNA processing, RNA splicing, and regulation of the mRNA metabolic process. KEGG analysis showed enrichment mainly in spliceosomes. We constructed a prognostic risk assessment model based on 11 autophagy-related genes in CRC.ConclusionA prognostic risk assessment model based on 11 autophagy-associated genes was constructed in CRC. The new model suggests directions and ideas for evaluating prognosis and provides guidance to choose better treatment strategies for CRC.

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Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer.

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Potentially functional genetic variants in KDR gene as prognostic markers in patients with resected colorectal cancer.

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