18 research outputs found
Serotonin Transporter Gene (<em>SLC6A4</em>) Variations Are Associated with Poor Survival in Colorectal Cancer Patients
<div><p>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 (<em>SLC6A4</em>), brain-derived neurotrophic factor (<em>BDNF</em>), and arginine vasopressin receptor (<em>AVPR1B</em>) 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 <em>SLC6A4</em> 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 <em>SLC6A4</em> 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 <em>SLC6A4</em> gene contribute to poor survival in colorectal cancer patients.</p> </div
Genes and SNPs investigated in this study.
<p>Summary of the genetic variations included in this study. <b>MAF:</b> minor allele frequency, <b>SNP ID:</b> dbSNP database <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038953#pone.0038953-Sherry1" target="_blank">[41]</a> SNP identifiers.</p
Kaplan-Meier survival curves for the combined genotypes of three <i>SLC6A4</i> polymorphisms.
<p> <b>a)</b> OS (p = 0.005, log-rank test), <b>b)</b> DFS (p = 0.104, log-rank test), and <b>c)</b> DSS (p = 0.008, log-rank test). Time is shown in years.</p
Multivariate analysis results for the combined genotypes of three SNPs within the <i>SLC6A4</i> gene (DSS).
<p>Multivariate analysis results for disease-specific survival. <b>(+):</b> patients with at least one minor (variant) allele in any of the three <i>SLC6A4</i> SNPs, <b>(−):</b> patients who did not have the variant allele in any of the three <i>SLC6A4</i> SNPs, <b>DSS:</b> disease-specific survival.</p
Kaplan-Meier survival curves for patients grouped based on the <i>SLC6A4</i>-rs12150214 genotype data.
<p><b>a)</b> OS (p = 0.030, log-rank test), <b>b)</b> DFS (p = 0.225, log-rank test), and <b>c)</b> DSS (p = 0.159, log-rank test). Time is shown in years.</p
The 5-HTT activity may be altered as a response to changing cellular environment (such as inflammation) or by the genetic variations in the <i>SLC6A4</i> gene.
<p>The direct links between the altered 5-HTT activity as well as the depression and prognosis in colorectal cancer patients (arrows with broken lines) remain to be established by further studies.</p
Baseline characteristics of the patient cohort.
<p>Summary of the baseline characteristics of the study cohort. <b>(+):</b> present, <b>(−):</b> absent, <b>DFS:</b> disease-free survival, <b>DSS:</b> disease-specific survival, <b>MSI-H:</b> microsatellite instability-high, <b>MSI-L:</b> microsatellite instability-low, <b>MSS:</b> microsatellite stable, <b>n:</b> number of samples included into the analysis, <b>OS:</b> overall survival.</p
Univariate analysis results for the combined genotypes of three SNPs within the <i>SLC6A4</i> gene.
<p>In the combined analysis, patients with at least one minor (variant) allele in any of the three SNPs in <i>SLC6A4</i> were categorized together (+) and were compared with the patients who did not have the variant alleles at these polymorphic loci (−). <b>OS:</b> overall survival, <b>DFS:</b> disease-free survival, <b>DSS:</b> disease-specific survival.</p
Multivariate analysis results for the combined genotypes of three SNPs within the <i>SLC6A4</i> gene (OS).
<p>Multivariate analysis results for overall survival. <b>(+):</b> patients with at least one minor (variant) allele in any of the three <i>SLC6A4</i> SNPs, <b>(−):</b> patients who did not have the variant allele in any of the three <i>SLC6A4</i> SNPs, <b>OS:</b> overall survival.</p
Proposed model for genetic susceptibility to DNA methylation in sporadic MSI-H CRCs.
<p>Specific SNPs predispose the region, including the <i>MLH1</i> gene promoter, to methylation, which results in promoter silencing and loss of <i>MLH1</i> gene expression that is measured by immunohistochemical staining. Loss of the <i>MLH1</i> gene expression leads to genome-wide microsatellite instability and MSI-H colorectal cancer.</p