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In this study, we aimed to investigate the associations of genetic variations within select genes functioning in angiogenesis, lymph-angiogenesis, and metastasis pathways and the risk of outcome in colorectal cancer patients. We followed a two-stage analysis: First, 381 polymorphisms from 30 genes (eight Vascular Endothelial Growth Factor ( VEGF) and 22 Matrix Metalloproteinase [ MMP] genes) were investigated in the discovery cohort ( n = 505). Then, 16 polymorphisms with the lowest P-value in this analysis were investigated in a separate replication cohort ( n = 247). Genotypes were obtained using the Illumina® HumanOmni-1-Quad (discovery cohort) and Sequenom MassArray® (replication cohort) platforms. The primary outcome measure was overall survival ( OS). Kaplan-Meier, univariate and multivariable Cox regression methods were used to test the associations between genotypes and OS. Four SNPs (rs12365082, rs11225389, rs11225388, and rs2846707) had the univariate analysis P < 0.05 in both the discovery and replication cohorts. These SNPs are in linkage disequilibrium with each other to varying extent and are located in the MMP8 and MMP27 genes. In the multivariable analysis adjusting for age, stage, and microsatellite instability status, three of these SNPs (rs12365082, rs11225389, rs11225388) were independent predictors of OS ( P < 0.05) in the discovery cohort. However, the same analysis in the replication cohort did not yield statistically significant results. Overall, while the genetic variations in the VEGF and MMP genes are attractive candidates as prognostic markers, our study showed no evidence of associations of a large set of SNPs in these genes and overall survival of colorectal cancer patients in our study. [ABSTRACT FROM AUTHOR]

Prognosis in colorectal cancer patients is quite variable, even after adjustment for clinical parameters such as disease stage and microsatellite instability status. It is possible that the psychological distress experienced by patients, including anxiety and depression, may be correlated with poor prognosis. In the present study, we hypothesize that genetic variations within three genes biologically linked to the stress response, namely serotonin transporter (SLC6A4), brain-derived neurotrophic factor (BDNF), and arginine vasopressin receptor (AVPR1B) genes are associated with prognosis in colorectal cancer patients. We used a population-based cohort of 280 patients who were followed for up to 12.5 years after diagnosis. Our multivariate analysis showed that a tagSNP in the SLC6A4 gene (rs12150214) was a predictor of shorter overall survival (HR: 1.572, 95%CI: 1.142-2.164, p = 0.005) independent of stage, age, grade and MSI status. Additionally, a multivariate analysis using the combined genotypes of three polymorphisms in this gene demonstrated that the presence of any of the minor alleles at these polymorphic loci was an independent predictor of both shorter overall survival (HR: 1.631, 95%CI: 1.190-2.236, p = 0.002) and shorter disease specific survival (HR: 1.691, 95%CI: 1.138-2.512, p = 0.009). The 5-HTT protein coded by the SLC6A4 gene has also been implicated in inflammation. While our results remain to be replicated in other patient cohorts, we suggest that the genetic variations in the SLC6A4 gene contribute to poor survival in colorectal cancer patients. [ABSTRACT FROM AUTHOR]