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Serotonin transporter gene (SLC6A4) variations are associated with poor survival in colorectal cancer patients.

Savas S, Hyde A, Stuckless SN, Parfrey P, Younghusband HB, Green R - PLoS ONE (2012)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. savas@mun.ca

ABSTRACT
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.

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Kaplan-Meier survival curves for the combined genotypes of three SLC6A4 polymorphisms.a) OS (p = 0.005, log-rank test), b) DFS (p = 0.104, log-rank test), and c) DSS (p = 0.008, log-rank test). Time is shown in years.
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pone-0038953-g002: Kaplan-Meier survival curves for the combined genotypes of three SLC6A4 polymorphisms.a) OS (p = 0.005, log-rank test), b) DFS (p = 0.104, log-rank test), and c) DSS (p = 0.008, log-rank test). Time is shown in years.

Mentions: We also performed a genotype combination analysis for the three SNPs from the SLC6A4 gene. Patients with genotypes with at least one minor allele in any of the three SNPs were compared with patients who were homozygous for major alleles. Univariate analysis showed that the presence of at least one minor allele was associated with worse OS and DSS, but not with DFS in our cohort (Table 4; Figure 2). More interestingly, when adjusted for other variables, the presence of at least one minor allele was independently associated with both worse OS (HR: 1.631, 95%CI: 1.190–2.236, p = 0.002) and worse DSS (HR: 1.691, 95%CI: 1.138–2.512, p = 0.009) (Tables 5 and 6). These associations were stronger than those detected when SLC6A4-rs12150214 was analyzed alone (Table 3; Figures 1 and 2). The AIC calculations indicated that the addition of the SLC6A4-rs12150214 genotype into the multivariate models (both for OS and DSS) also containing age, stage, grade, and MSI status variables improved the model predictions (Table 7). However, the best improvement was detected when the model contained the combined SLC6A4 genotypes in addition to the clinical variables (Table 7). In addition, when compared to the DSS model, the model improvement was more profound in the OS model.


Serotonin transporter gene (SLC6A4) variations are associated with poor survival in colorectal cancer patients.

Savas S, Hyde A, Stuckless SN, Parfrey P, Younghusband HB, Green R - PLoS ONE (2012)

Kaplan-Meier survival curves for the combined genotypes of three SLC6A4 polymorphisms.a) OS (p = 0.005, log-rank test), b) DFS (p = 0.104, log-rank test), and c) DSS (p = 0.008, log-rank test). Time is shown in years.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404081&req=5

pone-0038953-g002: Kaplan-Meier survival curves for the combined genotypes of three SLC6A4 polymorphisms.a) OS (p = 0.005, log-rank test), b) DFS (p = 0.104, log-rank test), and c) DSS (p = 0.008, log-rank test). Time is shown in years.
Mentions: We also performed a genotype combination analysis for the three SNPs from the SLC6A4 gene. Patients with genotypes with at least one minor allele in any of the three SNPs were compared with patients who were homozygous for major alleles. Univariate analysis showed that the presence of at least one minor allele was associated with worse OS and DSS, but not with DFS in our cohort (Table 4; Figure 2). More interestingly, when adjusted for other variables, the presence of at least one minor allele was independently associated with both worse OS (HR: 1.631, 95%CI: 1.190–2.236, p = 0.002) and worse DSS (HR: 1.691, 95%CI: 1.138–2.512, p = 0.009) (Tables 5 and 6). These associations were stronger than those detected when SLC6A4-rs12150214 was analyzed alone (Table 3; Figures 1 and 2). The AIC calculations indicated that the addition of the SLC6A4-rs12150214 genotype into the multivariate models (both for OS and DSS) also containing age, stage, grade, and MSI status variables improved the model predictions (Table 7). However, the best improvement was detected when the model contained the combined SLC6A4 genotypes in addition to the clinical variables (Table 7). In addition, when compared to the DSS model, the model improvement was more profound in the OS model.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Discipline of Genetics, Faculty of Medicine, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Canada. savas@mun.ca

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus