Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk.
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ABSTRACT:
SUBMITTER: Hazra A
PROVIDER: S-EPMC2719293 | biostudies-literature | 2008 Nov
REPOSITORIES: biostudies-literature
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Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk.
Hazra Aditi A Fuchs Charles S CS Chan Andrew T AT Giovannucci Edward L EL Hunter David J DJ
Cancer causes & control : CCC 20080514 9
We evaluated the association of a polymorphism in TCF7L2 (RS12255372) in the WNT signaling pathway, which previously has been strongly associated with risk of Type II Diabetes, with colorectal cancer (CRC) and adenoma in the prospective Nurses' Health Study (NHS) and Health Professionals Follow-up Study (HPFS) cohorts. Hyperinsulinemia may be related to the risk of colon adenoma and cancer, therefore this variant associated with reduced insulin secretion would be predicted to be inversely associ ...[more]
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Project description:ObjectiveThe transcription factor 7-like 2 (TCF7L2) gene has been suggested to play an important role in the pathogenesis of cancer. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the associations between TCF7L2 polymorphism and cancer risk.MethodsPublished literature from PubMed and EMBASE were retrieved. Pooled odds ratios (ORs) with 95% confidence interval (CIs) were calculated using fixed- or random-effects model.ResultsA total of 19 studies (14,814 cases and 33,856 controls) were identified for the analysis of the association between TCF7L2 polymorphism and cancer risk. The results showed that TCF7L2 polymorphism was associated with breast cancer (Homogeneous model: OR=1.17, 95%CI=1.02-1.35, I (2) =21.8%, p for heterogeneity=0.276; Heterogeneous model: OR=1.11, 95%CI=1.03-1.20, I (2) =0.0%, p for heterogeneity=0.543), prostate cancer (Homogeneous model: OR=0.89, 95%CI=0.84-0.96, I (2) =0.0%, p for heterogeneity=0.640; Heterogeneous model: OR=0.89, 95%CI=0.84-0.95, I (2) =0.0%, p for heterogeneity=0.871), and colon cancer (Heterogeneous model: OR=1.15, 95%CI=1.01-1.31, I (2) =0.0%, p for heterogeneity=0.658), but not with colorectal cancer, lung cancer, and ovarian cancer.ConclusionsThe present meta-analysis indicated that there were significantly associations between the TCF7L2 rs7903146 polymorphism and risk of breast, prostate and colon cancers, rather than colorectal cancer, lung cancer, and ovarian cancer.
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Project description:Methionine synthase (MTR), which plays a central role in maintaining adequate intracellular folate, methionine and normal homocysteine concentrations, was thought to be involved in the development of colorectal cancer (CRC) and colorectal adenoma (CRA) by affecting DNA methylation. However, studies on the association between MTR A2756G polymorphism and CRC/CRA remain conflicting. We conducted a meta-analysis of 27 studies, including 13465 cases and 20430 controls for CRC, and 4844 cases and 11743 controls for CRA. Potential sources of heterogeneity and publication bias were also systematically explored. Overall, the summary odds ratio of G variant for CRC was 1.03 (95% CI: 0.96-1.09) and 1.05 (95% CI: 0.99-1.12) for CRA. No significant results were observed in heterozygous and homozygous when compared with wild genotype for these polymorphisms. In the stratified analyses according to ethnicity, source of controls, sample size, sex, and tumor site, no evidence of any gene-disease association was obtained. Results from the meta-analysis of four studies on MTR stratified according to smoking and alcohol drinking status showed an increased CRC risk in heavy smokers (OR = 2.06, 95% CI: 1.32-3.20) and heavy drinkers (OR = 2.00, 95% CI: 1.28-3.09) for G allele carriers. This meta-analysis suggests that the MTR A2756G polymorphism is not associated with CRC/CRA susceptibility and that gene-environment interaction may exist.
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Project description:Colorectal cancer (CRC) is a heterogeneous disease with an increasing trend and with multiple epigenetic alterations and different molecular features, a major cause of mortality and morbidity. The Wnt/β-Catenin pathway is involved in multiple aspects of cell dynamics, architecture of developing gastrointestinal tissues, and intestinal tissue homeostasis in adults, but its aberrant activity plays an important role in every aspect of colorectal carcinogenesis. The aim of our study was to investigate the association of the TCF7L2 rs7903146, CASC8 rs6983267, and Gremlin1 (GREM1) rs16969681 polymorphism in patients with CRC without other pathologies. A case-control study conducted on 31 patients diagnosed with CRC and 30 healthy controls age and sex-matched with the patients. Real time PCR was used to determine the genotypes of rs7903146, rs698267, rs1696981. We observed no association between rs6983267 and rs16969681 polymorphism and risk of CRC and low association between TCF7L2, rs7903146, polymorphism and risk of CRC. The recessive model of the TCF7L2 rs7903146 had an OR of 1.6 (95% CI 0.058-4.414, P < .05) which means that TT genotype increased the risk and possibility of development of CRC. Our study did not confirm a significant association between TCF7L2 rs7903146, CASC8 rs6983267, and GREM1 rs16969681 with CRC, but emphasizes the possibility of existence of a high risk of CRC development in patients with TT genotype of rs7903146.
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Project description:Inflammatory processes, including, specifically, the inflammatory conditions Crohn's disease (CD) and ulcerative colitis (UC) predispose to colorectal cancer. Interleukin-23 is involved in pro-inflammatory signaling; genetic variation in the interleukin-23 receptor (IL23R) has been consistently associated with CD and UC risk. In three case-control studies of colorectal adenoma (n=485 cases/578 controls), colon cancer (n=1424 cases/1780 controls) and rectal cancer (n=583 cases/775 controls), we investigated associations with 18 candidate and tagSNPs in IL23R. The three studies used an identical Illumina GoldenGate assay, allowing thorough investigation across stages and locations of colorectal neoplasia. We further explored associations with molecular cancer subtypes (MSI+, CIMP+, KRAS2mut, TP53mut). In this comprehensive study of genetic variability in IL23R across the spectrum of colorectal carcinogenesis, as well as within colon and rectal tumor molecular subtypes, we observed associations between SNPs in IL23R and risk of rectal cancer: the 88413 C>A (rs10889675) and 69450 C>A (rs7542081) polymorphisms were associated with decreased rectal cancer risk overall (p-trend=0.04 and 0.05 respectively), and specifically with rectal tumors bearing a TP53 mutation (88413 CA/AA vs. CC OR: 0.66; 95% CI: 0.46-94; 69450 CA/AA vs. CC OR: 0.60; 95% CI: 0.37-0.98). However, none of associations remained statistically significant after correction for multiple testing. These data provide some evidence that genetic variability in IL23R may contribute to rectal cancer risk and should be evaluated in additional studies.
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Project description:The multidrug resistance gene 1(MDR1) C3435T polymorphism has been reported to be associated with colorectal cancer (CRC) risk in Asians, however the results were inconsistent. Thus, we performed a meta-analysis to generate large-scale evidence on the association between C3435T polymorphism and CRC risk in Asian populations.The PubMed, Web of Science, Embase, CNKI, and Chinese Biomedicine databases were searched up to January 15, 2017. The odd ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by a fixed-effects or random-effects model. Sensitivity and cumulative meta-analysis were also performed.A total of 7 studies involving 4818 individuals were included in this pooled-analysis. The results suggested that persons carrying a T allele at the C3435T polymorphism had a significantly decreased risk of CRC in Asian population (T vs C: OR?=?0.897, 95%CI?=?0.826-0.975, P?=?.01), and the significant association was also observed in another 2 genetic models (TT vs CC: OR?=?0.721, 95%CI?=?0.605-0.861, P?<?.001; TT vs TC+CC: OR?=?0.679, 95%CI?=?0.579-0.795, P?<?.001). Moreover, the results of sensitivity and cumulative meta-analysis indicated the stable of our results. Finally, funnel plot and Egger's test showed no evidence of publication bias.In summary, this meta-analysis provided evidence that MDR1 C3435T polymorphism is associated with a decreased risk of CRC in Asian population.
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Project description:The proportion of screening colonoscopic examinations performed by a physician that detect one or more adenomas (the adenoma detection rate) is a recommended quality measure. However, little is known about the association between this rate and patients' risks of a subsequent colorectal cancer (interval cancer) and death.Using data from an integrated health care delivery organization, we evaluated the associations between the adenoma detection rate and the risks of colorectal cancer diagnosed 6 months to 10 years after colonoscopy and of cancer-related death. With the use of Cox regression, our estimates of attributable risk were adjusted for the demographic characteristics of the patients, indications for colonoscopy, and coexisting conditions.We evaluated 314,872 colonoscopies performed by 136 gastroenterologists; the adenoma detection rates ranged from 7.4 to 52.5%. During the follow-up period, we identified 712 interval colorectal adenocarcinomas, including 255 advanced-stage cancers, and 147 deaths from interval colorectal cancer. The unadjusted risks of interval cancer according to quintiles of adenoma detection rates, from lowest to highest, were 9.8, 8.6, 8.0, 7.0, and 4.8 cases per 10,000 person-years of follow-up, respectively. Among patients of physicians with adenoma detection rates in the highest quintile, as compared with patients of physicians with detection rates in the lowest quintile, the adjusted hazard ratio for any interval cancer was 0.52 (95% confidence interval [CI], 0.39 to 0.69), for advanced-stage interval cancer, 0.43 (95% CI, 0.29 to 0.64), and for fatal interval cancer, 0.38 (95% CI, 0.22 to 0.65). Each 1.0% increase in the adenoma detection rate was associated with a 3.0% decrease in the risk of cancer (hazard ratio, 0.97; 95% CI, 0.96 to 0.98).The adenoma detection rate was inversely associated with the risks of interval colorectal cancer, advanced-stage interval cancer, and fatal interval cancer. (Funded by the Kaiser Permanente Community Benefit program and the National Cancer Institute.).
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Project description:ImportanceIndividuals with adenomatous polyps are advised to undergo repeated colonoscopy surveillance to prevent subsequent colorectal cancer (CRC), but the relationship between adenomas at colonoscopy and long-term CRC incidence is unclear.ObjectiveTo compare long-term CRC incidence by colonoscopy adenoma findings.Design, setting, and participantsMulticenter, prospective cohort study of participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer randomized clinical trial of flexible sigmoidoscopy (FSG) beginning in 1993 with follow-up for CRC incidence to 2013 across the United States. Participants included 154 900 men and women aged 55 to 74 years enrolled in PLCO of whom 15 935 underwent colonoscopy following their first positive FSG screening result. The final day of follow-up was December 31, 2013.ExposuresEnrolled participants had been randomized to FSG or usual care. Participants who underwent FSG and had abnormal findings were referred for follow-up. Subsequent colonoscopy findings were categorized as advanced adenoma (≥1 cm, high-grade dysplasia, or tubulovillous or villous histology), nonadvanced adenoma (<1 cm without advanced histology), or no adenoma.Main outcomes and measuresThe primary outcome was CRC incidence within 15 years of the baseline colonoscopy. The secondary outcome was CRC mortality.ResultsThere were 15 935 participants who underwent colonoscopy (men, 59.7%; white, 90.7%; median age, 64 y [IQR, 61-68]). On initial colonoscopy, 2882 participants (18.1%) had an advanced adenoma, 5068 participants (31.8%) had a nonadvanced adenoma, and 7985 participants (50.1%) had no adenoma; median follow-up for CRC incidence was 12.9 years. CRC incidence rates per 10 000 person-years of observation were 20.0 (95% CI, 15.3-24.7; n = 70) for advanced adenoma, 9.1 (95% CI, 6.7-11.5; n = 55) for nonadvanced adenoma, and 7.5 (95% CI, 5.8-9.7; n = 71) for no adenoma. Participants with advanced adenoma were significantly more likely to develop CRC compared with participants with no adenoma (rate ratio [RR], 2.7 [95% CI, 1.9-3.7]; P < .001). There was no significant difference in CRC risk between participants with nonadvanced adenoma compared with no adenoma (RR, 1.2 [95% CI, 0.8-1.7]; P = .30). Compared with participants with no adenoma, those with advanced adenoma were at significantly increased risk of CRC death (RR, 2.6 [95% CI, 1.2-5.7], P = .01), but mortality risk in participants with nonadvanced adenoma was not significantly different (RR, 1.2 [95% CI, 0.5-2.7], P = .68).Conclusions and relevanceOver a median of 13 years of follow-up, participants with an advanced adenoma at diagnostic colonoscopy prompted by a positive flexible sigmoidoscopy result were at significantly increased risk of developing colorectal cancer compared with those with no adenoma. Identification of nonadvanced adenoma may not be associated with increased colorectal cancer risk.Trial registrationclinicaltrials.gov Identifier: NCT00002540.
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