Polymorphisms in PTGS1, PTGS2 and IL-10 do not influence colorectal adenoma recurrence in the context of a randomized aspirin intervention trial

Section of Cancer Genetics, Institute of Cancer Research, Sutton SM2 5NG, United Kingdom.
International Journal of Cancer (Impact Factor: 5.01). 11/2007; 121(9):2001-4. DOI: 10.1002/ijc.22942
Source: PubMed

ABSTRACT Regular use of aspirin and other nonsteroidal antiinflammatory drugs reduces both the development of colorectal neoplasia and recurrence of colorectal adenoma (CRA). Modulation of the effects of aspirin by genetic factors has been reported, potentially allowing targeting of treatment to individuals most likely to gain benefit. Prostaglandin H synthase 1 (PTGS1) and PTGS2 are key enzymes in prostaglandin synthesis and are inhibited by aspirin, whilst interleukin-10 (IL-10) is an important antiinflammatory cytokine. We investigated whether functional genetic polymorphisms in the PTGS1, PTGS2 and IL-10 genes influence CRA recurrence in individuals participating in a randomized aspirin intervention trial. DNA was available for genotyping from 546 patients who received aspirin (300 mg daily) or placebo for a mean 41-months' duration. Homozygote carriers of variant alleles for the PTGS1 50C>T, PTGS2 -765G>C and IL-10 -592C>A polymorphisms did not have a significantly altered risk of CRA recurrence (relative risk [RR]=0.91; 95% confidence interval [CI]: 0.14-6.07, RR=1.32; 95% CI: 0.66-2.62 and RR=1.24; 95% CI: 0.74-2.07, respectively). There were also no significant interactions between aspirin intervention and genotype in determining recurrence risk. These data indicate that these polymorphisms are unlikely to influence CRA recurrence and cannot be used to identify individuals who derive benefit from aspirin intervention.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract The aim of the present work was to perform a meta-analysis to evaluate the association between the interleukin 10 (IL-10) -819C/T (rs1800871) polymorphism and cancer risk. A total of 73 studies, including 15,942 cancer cases and 22,336 controls, were identified in this meta-analysis. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Overall, no significant association was identified between the IL-10 -819C/T polymorphism and cancer risk. In the subgroup analyses, the T allele and TT genotype were associated with a moderately reduced cancer risk in the Asian population (T allele vs. C allele: OR=0.93, 95%CI: 0.87, 0.99; TT vs. CC: OR=0.86, 95%CI: 0.76, 0.98; TT vs. CT/CC: OR=0.90, 95%CI: 0.82, 0.98). Individuals who were homozygous for the T allele (TT) were found to be associated with significantly reduced gastric cancer risk in the Asian population. The heterozygous variant (CT) and the dominant model (TT/CT vs. CC) were associated with an increased risk for cervical and ovarian cancer. However, the IL-10 -819C/T polymorphism was not significantly associated with breast cancer, colorectal cancer, lung cancer, hepatocellular carcinoma, prostate cancer, lymphoma, or melanoma. The depressed cancer risk of the TT genotype occurred in the studies of hospital-based case-control studies and the studies recruited less than 500 subjects, but no statistically significant results were found in the stratified analyses using genotyping method. The results suggest that the IL-10 -819TT genotype may be a protective factor for cancer in Asians, especially gastric cancer. In contrast, the CT genotype and the dominant model could be risk factors for cervical and ovarian cancer. The importance of stratifying by ethnicity, cancer type, study design, and sample size needs to be standardized in future studies, together with considering the association between the IL-10 -819C/T polymorphism and cancer risk. Furthermore, the linkage of -819C/T with other polymorphisms of the IL-10 gene may help explain the variability in findings.
    Omics: a journal of integrative biology 04/2013; 17(4):200-14. DOI:10.1089/omi.2012.0089 · 2.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background Colorectal cancer is a major global public health problem, with approximately 950 000 patients newly diagnosed each year. We report the first comprehensive field synopsis and creation of a parallel publicly available and regularly updated database (CRCgene) that catalogs all genetic association studies on colorectal cancer ( Methods We performed two independent systematic reviews, reviewing 10 145 titles, then collated and extracted data from 635 publications reporting on 445 polymorphisms in 110 different genes. We carried out meta-analyses to derive summary effect estimates for 92 polymorphisms in 64 different genes. For assessing the credibility of associations, we applied the Venice criteria and the Bayesian False Discovery Probability (BFDP) test. Results We consider 16 independent variants at 13 loci (MUTYH, MTHFR, SMAD7, and common variants tagging the loci 8q24, 8q23.3, 11q23.1, 14q22.2, 1q41, 20p12.3, 20q13.33, 3q26.2, 16q22.1, and 19q13.1) to have the most highly credible associations with colorectal cancer, with all variants except those in MUTYH and 19q13.1 reaching genome-wide statistical significance in at least one meta-analysis model. We identified less-credible (higher heterogeneity, lower statistical power, BFDP >0.2) associations with 23 more variants at 22 loci. The meta-analyses of a further 20 variants for which associations have previously been reported found no evidence to support these as true associations. Conclusion The CRCgene database provides the context for genetic association data to be interpreted appropriately and helps inform future research direction.
    CancerSpectrum Knowledge Environment 09/2012; 104(19):1433-57. DOI:10.1093/jnci/djs369 · 15.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several studies have investigated whether the polymorphisms in the prostaglandin endoperoxide synthase 1 (PTGS1) and PTGS2 genes and nonsteroidal anti-inflammatory drug (NSAID) use are associated with cancer risk; however, those studies have produced mixed results. Therefore, we performed a meta-analysis to evaluate the association between the PTGS1 and PTGS2 polymorphisms and the effect of NSAID use on the risk of developing cancer. We conducted a comprehensive search in PubMed through March 2012. The odds ratios (ORs) with the corresponding 95% confidence intervals (CIs) were calculated using the fixed-effect model or the random-effect model. The database search generated 13 studies that met the inclusion criteria. For PTGS1 rs3842787, NSAID users homozygous for the major allele (CC) had a significantly decreased cancer risk compared with non-NSAID users (OR = 0.73, 95% CI = 0.59-0.89). For PTGS2 rs5275 and rs20417, there were no significant differences between the gene polymorphism and NSAID use on cancer risk among the 8 and 7 studies, respectively. However, in the stratified analysis by the type of cancer or ethnicity population, NSAID users homozygous for the major allele (TT) in rs5275 demonstrated significantly decreased cancer risk compared with non-NSAID users in cancer type not involving colorectal adenoma (OR = 0.70, 95% CI = 0.59-0.83) and among the USA population (OR = 0.67, 95% CI = 0.56-0.82). NSAID users homozygous for the major allele (GG) in rs20417 displayed a significantly decreased cancer risk than non-NSAID users among the US population (OR = 0.72, 95% CI = 0.58-0.88). For the PTGS2 rs689466 and rs2745557 SNPs, there were no significant differences. This meta-analysis suggests that the associations between PTGS polymorphisms and NSAID use on cancer risk may differ with regard to the type of cancer and nationality.
    PLoS ONE 08/2013; 8(8):e71126. DOI:10.1371/journal.pone.0071126 · 3.53 Impact Factor

Full-text (2 Sources)

Available from
Oct 6, 2014