Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P < 0.0026 and a power of 90%. Eighteen polymorphisms in 15 genes were each described in only one study, all with very small sample sizes. For 11 polymorphisms in 10 of these genes, an association with colorectal adenoma and/or cancer was found. Only simultaneous genotyping and combined analysis of different polymorphisms in large numbers of patients and controls, stratified by ethnicity, gender, and tumor localization and taking relevant dietary and lifestyle habits into account, will make it possible to describe the exact relations between polymorphisms and colorectal cancer susceptibility with an adequate power.
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PMID:Low-penetrance genes and their involvement in colorectal cancer susceptibility. 1243 10

An increased occurrence of colorectal cancer and its adenoma precursor is observed among individuals with low intakes or circulating levels of folate, especially if alcohol intake is high, although results have not been statistically significant in all studies. We examined folate and alcohol intake and genetic polymorphisms in methylenetetrahydrofolate reductase [MTHFR 667-->T (ala-->val) and MTHFR 1298A-->C (gln-->ala)] (associated with reduced MTHFR activity) and in alcohol dehydrogenase 3 [ADH3 (2-2) associated with decreased alcohol catabolism] in relation to risk of colorectal adenoma in the Health Professionals Follow-Up Study. Among 379 cases and 726 controls, MTHFR genotypes were not appreciably related to risk of adenoma, but a suggestive interaction (P = 0.09) was observed between MTHFR 677C-->T and alcohol intake; men with TT homozygotes who consumed 30+ g/day of alcohol had an odds ratio (OR) of 3.52 [95% confidence interval (CI), 1.41-8.78] relative to drinkers of < or =5 g/day with the CC/CT genotypes. ADH3 genotype alone was not appreciably related to risk, but its influence was modified by alcohol intake. Compared with fast alcohol catabolizers [ADH3(1-1)] with low intakes of alcohol (< or =5 g/day), high consumers of alcohol (30+ g/day) had a marked increase in risk if they had the genotype associated with slow catabolism [ADH3(2-2); OR, 2.94; 95% CI, 1.24-6.92] or intermediate catabolism [ADH3(1-2)] of alcohol (OR, 1.83; 95% CI, 1.03-3.26) but not if they were fast catabolizers [ADH3(1-1); OR = 1.27; 95% CI = 0.63-2.53). In addition, an increased risk of colorectal adenoma (OR, 17.1; 95% CI, 2.1-137) was observed for those with the ADH3(2-2) genotype and high alcohol-low folate intake compared with those with low alcohol-high folate intake and the ADH3(1-1) genotype (P for interaction = 0.006). Our results indicate that high intake of alcohol is associated with an increased risk of colorectal adenoma, particularly among MTHFR 677TT and ADH3(2-2) homozygotes. The findings that alcohol interacts with a folate-related gene (MTHFR) and that the interaction between alcohol and ADH3 is stronger among those with low folate intake support the hypothesis that the carcinogenic influence of alcohol in the large bowel is mediated through folate status.
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PMID:Methylenetetrahydrofolate reductase, alcohol dehydrogenase, diet, and risk of colorectal adenomas. 1457 31

So far, evidence for the relation between folate intake and colorectal cancer has been insufficient to lead to specific public health interventions. In principle, data on the relation between genetic variation in folate metabolism and colorectal neoplasia could be used to corroborate the data on the relation between folate intake or status and the disease, strengthening the evidence base for primary prevention. Issues in considering the relation between a health outcome and genetic variation in metabolism of nutrients or other food components include knowledge of gene function, linkage disequilibrium, population stratification, study size and quality, and gene-environment interaction. Overall homozygosity for MTHFR variant genotypes is associated with a reduced risk of colorectal cancer, the opposite of what might have been expected a priori. This has led investigators to place greater emphasis on the functions of folate and methylenetetrahydrofolate reductase in DNA synthesis. Folate and related nutrients may be important after adenoma formation. A challenge for the future is to characterize the effects of multiple genes influencing folate metabolism. Limited data for colorectal cancer suggest that the effect of a low folate diet overrides the effect of genotype, but two studies of adenomas suggested the opposite. Another potential role of information on genetic variation in folate metabolism is in the management of colorectal cancer but most studies have been small, have included selected patient groups, and have made limited adjustment for potentially important factors.
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PMID:Colon cancer and genetic variation in folate metabolism: the clinical bottom line. 1460 11

Methionine synthase [5-methyltetrahydrofolate-homocysteine S-methyltransferase (MTR)] is involved in folate-mediated one-carbon metabolism, a pathway known to play a role in colorectal carcinogenesis. We investigated whether the MTR D919G polymorphism was associated with risk of colorectal adenoma in a colonoscopy-based study of 513 cases and 609 controls from Minneapolis, MN. Adenoma risk appeared nonsignificantly increased among women with DG or GG genotype [adjusted odds ratio (OR) versus DD, 1.4; 95% confidence interval (CI), 0.9-2.1] but not men (OR, 1.0; 95% CI, 0.7-1.5). An interaction with methionine intake was observed among women, such that low versus high intake was associated with a 2.3-fold increased risk only among those with DG or GG genotype (95% CI, 1.1-4.9; P for interaction = 0.05). Similarly, risk associated with alcohol intake was not elevated among women with the DD genotype; however, consumption of >7 g of alcohol/day versus none was associated with an increased risk among women with DG or GG genotype (adjusted OR, 2.5; 95% CI, 1.4-4.4; P for interaction = 0.03). An interaction between MTR D919G and the thymidylate synthase (TS or TYMS) 3'-untranslated region polymorphism 1494del6 was also observed among women (P for interaction = 0.007). No evidence of interaction with intake of folate, vitamin B(12), or vitamin B(6) or with genotype at MTHFR C677T or the TS enhancer region 28-bp repeat polymorphism was seen. These findings add to what is known about the complexities of genetic variations in one-carbon-metabolizing enzymes in relation to colorectal carcinogenesis.
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PMID:Methionine synthase D919G polymorphism, folate metabolism, and colorectal adenoma risk. 1474 49

Thymidylate synthase (TS), a key one-carbon metabolizing gene, encodes an enzyme that converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. We recently reported that a promoter polymorphism in TS modified the risk of colorectal cancer as well as the survival rate after the disease. To explore whether TS may play an important role in colorectal carcinogenesis early in the multistaged pathogenic pathway, we investigated the relation between the TS promoter polymorphism and risk of colorectal adenoma in a nested case-control study within the prospective Health Professionals Follow-up Study. We ascertained the TS genotype from 373 incident colorectal adenoma cases and 720 control subjects. Although there was no overall association between the TS promoter polymorphism and adenoma risk, we observed a significant TS-alcohol interaction (P for interaction = 0.009); relative to low alcohol consumers with the 2R/2R genotype, those with high alcohol consumption (>30 g/d) were not at elevated risk if they had the 2R/2R genotype [relative risk (RR), 0.80; 95% confidence interval (95% CI), 0.34-1.90], but were at higher risk if they had the 2R/3R genotype (RR, 1.70; 95% CI, 0.87-3.31), and at the highest risk (RR, 3.16; 95% CI, 1.50-6.63) if they had the 3R/3R genotype. In addition, a significant interaction was observed between the TS promoter polymorphism and the 677C > T polymorphism of methylenetetrahydrofolate reductase (MTHFR; P for interaction = 0.007). These findings lend additional support that one-carbon metabolism is an important process in pathogenesis of colorectal cancer.
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PMID:Polymorphism in the thymidylate synthase promoter enhancer region and risk of colorectal adenomas. 1559 87

We investigated the associations between dietary intake of folate and vitamin B2, MTHFR C677T genotype, and colorectal adenomas in a Dutch case-control study. Data of cases with at least one histologically confirmed colorectal adenoma (n = 768) and controls with no history of any type of colorectal polyp (n = 709) were included. Dietary intake was assessed using a food-frequency questionnaire. Multivariable models included age and, if appropriate, dietary folate and calcium intake. The adjusted odds ratio (OR) and 95% confidence interval (CI) for the highest compared with the lowest sex-specific tertile of intake were 1.32 (95% CI, 1.01-1.73) for folate and 0.51 (95% CI, 0.36-0.73) for vitamin B2. Folate seemed to be a risk factor, especially when vitamin B2 intake was low; vitamin B2 was inversely associated with adenomas, especially with relatively high folate intake. No association was observed between MTHFR C677T genotype and colorectal adenomas. The inverse association between vitamin B2 intake and colorectal adenoma risk seemed to be more pronounced among those with the MTHFR TT genotype. We conclude that this study does not provide evidence for a decreased colorectal adenoma risk for subjects with high dietary intake of folate. It suggests, however, an inverse association between vitamin B2 and colorectal adenomas, which may be more relevant for those with the MTHFR TT genotype.
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PMID:Dietary intake of folate and riboflavin, MTHFR C677T genotype, and colorectal adenoma risk: a Dutch case-control study. 1594 73

Methylenetetrahydrofolate reductase is a key enzyme in folate metabolism, which affects DNA synthesis and methylation and is possibly linked to colorectal carcinogenesis. Alcohol and acetaldehyde have an adverse effect on folate metabolism. This study investigated the relationship of functional MTHFR C677T and ALDH2 polymorphisms to colorectal adenomas with reference to alcohol consumption in a case-control study of male officials in the Self-Defense Forces (SDF) who received a preretirement health examination at two SDF hospitals. The study subjects were 452 cases of colorectal adenoma and 1050 controls with no polyp who underwent total colonoscopy. Genotypes were determined by the PCR-RFLP method using genomic DNA extracted from the buffy coat. Statistical adjustment was made for age, hospital, rank in the SDF, body mass index, cigarette-years and alcohol intake. Neither MTHFR C677T nor ALDH2 showed a measurable association with colorectal adenoma. While high alcohol consumption was associated with a moderately increased risk of colorectal adenoma, neither of the two polymorphisms showed a significant effect on the association between alcohol and colorectal adenoma. Individuals with the variant alleles ALDH2*2 and MTHFR 677T had a decreased risk of colorectal adenomas, showing adjusted odds ratios of 0.70 (95% confidence interval 0.49-1.00) for all adenomas and 0.57 (0.34-0.95) for large adenomas (> or = 5 mm), as compared to individuals with ALDH2*1/1 and MTHFR 677CC genotypes combined. The findings may be interpreted as suggesting that folate inhibits the growth of colorectal adenomas, but further confirmation is needed.
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PMID:Genetic polymorphisms of methylenetetrahydrofolate reductase and aldehyde dehydrogenase 2, alcohol use and risk of colorectal adenomas: Self-Defense Forces Health Study. 1610 33

Folate intake is inversely related to risk of developing colorectal neoplasia. Associations between risk of colorectal neoplasia and polymorphisms in genes coding for enzymes involved in folate metabolism have also been reported, suggesting a relationship between genotype and development of colorectal neoplasia. To further investigate the effects of folate metabolism genotypes on colorectal neoplasia, we genotyped 546 patients participating in a randomized controlled trial of folate supplementation for the prevention of colorectal adenoma recurrence. A significantly reduced risk of recurrence was observed in patients heterozygous for the MTRR A66G polymorphism [relative risk (RR), 0.64; 95% confidence interval (95% CI), 0.46-0.90] or heterozygous for the MTHFR A1298C polymorphism (RR, 0.71; 95% CI, 0.52-0.97). Furthermore, a significant reduction in recurrence risk was seen in MTRR A66G heterozygotes who received folate supplements but not in those who did not receive folate. Patients heterozygous for the MTHFR C677T polymorphism had a nonsignificant risk reduction (RR, 0.92; 95% CI, 0.69-1.23), as did patients with one or two variant alleles for the MTR A2756G polymorphism (RR, 0.82; 95% CI, 0.60-1.12). No influence on recurrence risk was observed for the TSER, TSER 3R G>C, and TS 1494del6 variants. These findings provide additional support for the hypothesis that germ line variants in folate metabolism genes influence the development of colorectal adenomas.
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PMID:Folate metabolism polymorphisms influence risk of colorectal adenoma recurrence. 1698 20

Association studies on the MTHFR polymorphisms (C677T and A1298C) in colorectal cancer (CRC) and colorectal adenoma have shown conflicting results. We performed a meta-analysis to better assess the purported associations. Overall, the 677T allele (10,131 patients and 15,362 controls) showed a small but significant protective effect against CRC compared to the 677C allele [P=0.0003, odds ratio (OR)=0.93; 95% confidence interval (CI) 0.89-0.98, P=0.22 (for heterogeneity)] for a worldwide population. Meta-analyses of other genetic contrasts suggested that the 677T allele is more likely to affect CRC in a recessive genetic model worldwide (P<0.0001, OR=0.86; 95% CI 0.76-0.96, P=0.06) and in Asians (P=0.0005, OR=0.75; 95% CI 0.64-0.88, P=0.71). Similarly, we found a significantly decreased risk of CRC for 1298C polymorphism (4,764 CRC patients and 6,592 controls) for a recessive genetic model worldwide (P=0.005, OR=0.81; 95% CI 0.70-0.94, P=0.40) and in Caucasians (P=0.04, OR=0.75 95% CI 0.57-0.99, P=0.35). No evidence of association of C677T (4,616 patients and 6,338 controls) and A1298C (1,272 patients and 1,684 controls) with colorectal adenoma were found. The evidence accumulated suggests that MTHFR may represent a low-penetrance susceptible gene for CRC, and that the two polymorphisms might protect against colorectal adenoma developing into cancer. A larger single study is required to further evaluate gene-gene and gene-environment interactions for MTHFR polymorphisms and the cancer risk in a specific population.
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PMID:Different roles of MTHFR C677T and A1298C polymorphisms in colorectal adenoma and colorectal cancer: a meta-analysis. 1708 70

Methylation of the promoter region of tumor suppressor genes is increasingly recognized to play a role in cancer development through silencing of gene transcription. We examined the associations between dietary folate intake, MTHFR C677T genotype, and promoter methylation of six tumor suppressor and DNA repair genes. Patients with colorectal adenoma (n = 149) and controls (n = 286) with folate intake in the upper or lower tertile with the CC or TT genotype were selected from a case-control study. Methylation-specific PCRs were conducted on colorectal adenoma specimens. The percentages of promoter methylation ranged from 15.7% to 64.2%. In case-case comparisons, folate was inversely associated with promoter methylation, especially among TT homozygotes. Case-control comparisons suggested that folate was not associated with the occurrence of adenomas with promoter methylation, and increased the risk of unmethylated adenomas, especially in TT homozygotes. The interactions between folate and MTHFR genotype were most pronounced for O(6)-MGMT: compared with CC homozygotes with low folate intake, the adjusted odds ratios (95% confidence interval) of having a methylated O(6)-MGMT promoter were 3.39 (0.82-13.93) for TT homozygotes with low folate intake and 0.37 (0.11-1.29) for TT homozygotes with high folate intake (P interaction = 0.02); the odds ratios for the occurrence of adenomas without methylation were 0.57 (0.16-2.11) for TT homozygotes with low folate intake and 3.37 (1.17-9.68) for TT homozygotes with high folate intake (P interaction = 0.03). In conclusion, folate intake seems to be inversely associated with promoter methylation in colorectal adenomas in case-case comparisons, and was positively associated with the occurrence of adenomas without promoter methylation in case-control comparisons, especially for TT homozygotes.
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PMID:Dietary folate intake in combination with MTHFR C677T genotype and promoter methylation of tumor suppressor and DNA repair genes in sporadic colorectal adenomas. 1730 Dec 67


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