Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been proposed that dietary factors such as folate, alcohol and methionine may be associated with colon cancer because of their involvement in DNA methylation processes. Data from a large population-based case-control study of incident colon cancer were used to evaluate whether intake of dietary, obesity, physical activity and nonsteroidal antiinflammatory drugs are associated with a CpG island methylator phenotype (CIMP). The BRAF V600E mutation and 5 CpG island markers (MINT1, MINT2, MINT31, p16 and hMLH1) were assessed in 1154 cases of colon cancer. We hypothesized that dietary factors involved in DNA methylation, cruciferous vegetables and use of aspirin/NSAIDs would be associated with CIMP-high tumors. Dietary folate, vitamins B(6) and B(12), methionine and alcohol were not associated with increased likelihood of colon tumors with the CIMP-high (2 or more markers methylated) phenotype. Dietary fiber, physical activity and aspirin and other nonsteroidal antiinflammatory drugs were inversely associated with both CIMP-low and CIMP-high tumors. Our results also suggested non-CIMP pathways as well. Obese individuals were at 2-fold increased risk of having a CIMP-low tumor. Alcohol was associated with an increased risk of tumors that were MSI+ and CIMP-low. In the presence of smoking 20 or more cigarettes per day, use of NSAIDs did not protect against a BRAF mutation. Our data suggest multiple pathways to colon cancer. They do not support a unique role for dietary folate, alcohol, vitamins B(6) and B(12) and methionine in a CpG island methylator phenotype.
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PMID:Diet and lifestyle factor associations with CpG island methylator phenotype and BRAF mutations in colon cancer. 1709 26

This study investigated associations between CpG island methylator phenotype (CIMP) colon cancer and genetic polymorphisms relevant to one-carbon metabolism and thus, potentially the provision of methyl groups and risk of colon cancer. Data from a large, population-based case-control study (916 incident colon cancer cases and 1,972 matched controls) were used. Candidate polymorphisms in methylenetetrahydrofolate reductase (MTHFR), thymidylate synthase (TS), transcobalamin II (TCNII), methionine synthase (MTR), reduced folate carrier (RFC), methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), dihydrofolate reductase (DHFR) and alcohol dehydrogenase 3 (ADH3) were evaluated. CIMP- or CIMP+ phenotype was based on five CpG island markers: MINT1, MINT2, MINT31, p16 and MLH1. The influence of specific dietary factors (folate, methionine, vitamin B(12) and alcohol) on these associations was also analyzed. We hypothesized that polymorphisms involved in the provision of methyl groups would be associated with CIMP+ tumors (two or more of five markers methylated), potentially modified by diet. Few associations specific to CIMP+ tumors were observed overall, which does not support the hypothesis that the provision of methyl groups is important in defining a methylator phenotype. However, our data suggest that genetic polymorphisms in MTHFR 1,298A > C, interacting with diet, may be involved in the development of highly CpG-methylated colon cancers. AC and CC genotypes in conjunction with a high-risk dietary pattern (low folate and methionine intake and high alcohol use) were associated with CIMP+ (OR = 2.1, 95% CI = 1.3-3.4 versus AA/high risk; P-interaction = 0.03). These results provide only limited support for a role of polymorphisms in one-carbon metabolism in the etiology of CIMP colon cancer.
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PMID:Genetic polymorphisms in one-carbon metabolism: associations with CpG island methylator phenotype (CIMP) in colon cancer and the modifying effects of diet. 1744 6

To identify additional alterations to c-kit or platelet-derived growth factor receptor alpha (PDGFRA) genes in gastrointestinal stromal tumors (GIST), we investigated the methylation status of nine known methylation-sensitive CpG islands (p15, p16, p73, 0-6-methylguanine-DNA methyltransferase, E-cadherin, mutL homolog 1, colon cancer nonpolyposis type 2 (escherichia), methylated in tumors [MINT]1, MINT2, and MINT31), and compared the results with the malignant potential and gain-of-function mutation types of GIST. Thirty-five GIST (c-kit mutations in 25 cases, PDGFRA mutations in seven cases, and lacking either mutation in three cases) were subjected to methylation-specific polymerase chain reaction to detect the methylation status of the nine methylation-sensitive CpG islands. Aberrant DNA methylation of these loci was found in 94% of all GIST. The rates of DNA methylation at each locus were as follows: hMLH1, 60%; MINT2, 51%; MGMT, 49%; p73, 49%; p16, 20%; E-cadherin, 14%; MINT1, 9%; p15, 6%; and MINT31, 0%. CpG islands methylator phenotype, which was defined as methylation involving more than three gene promoters, was found in 57% of GIST with c-kit or PDGFRA gene mutations. According to the risk categories, CpG islands methylator phenotype was present in 55% of low-risk GIST, and in 58% of high-risk GIST. Our results suggested that in addition to c-kit or PDGFRA mutations, the aberrant methylation of CpG islands, especially of mismatch-repair genes, may have a role in the tumorigenesis of GIST.
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PMID:Aberrant methylation status of known methylation-sensitive CpG islands in gastrointestinal stromal tumors without any correlation to the state of c-kit and PDGFRA gene mutations and their malignancy. 1827 23

The MLH1 -93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the -93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The -93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 -93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 -93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway.
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PMID:The MLH1 -93 G>A promoter polymorphism and genetic and epigenetic alterations in colon cancer. 1861 80

The CpG island methylator phenotype (CIMP) is a distinct phenotype in colorectal cancer, associated with specific clinical, pathologic, and molecular features. However, most of the studies stratified methylation according to two subgroups (CIMP-High versus No-CIMP/CIMP-Low). In our study, we defined three different subgroups of methylation (No-CIMP, CIMP-Low, and CIMP-High) and evaluated the prognostic significance of methylation status on a population-based series of sporadic colon cancers. A total of 582 colon adenocarcinomas were evaluated using methylation-specific PCR for 5 markers (hMLH1, P16, MINT1, MINT2, and MINT31). No-CIMP status was defined as no methylated locus, CIMP-Low status as one to three methylated loci, and CIMP-High status as four or five methylated loci. Clinicopathologic and molecular characteristics were correlated to the methylation status. Crude and relative survival was compared according to methylation status. In the microsatellite-stable (MSS) group, CIMP-High was significantly associated with proximal location (P = 0.011) and BRAF mutation (P < 0.001). KRAS mutations were more associated with CIMP-High and CIMP-Low status (P = 0.008). A shorter 5-year survival was observed in MSS cancer patients with CIMP-Low or CIMP-High status. These results remained significant in multivariate analysis adjusted for age, stage, and BRAF and KRAS mutational status [CIMP-Low: hazard ratio (HR), 1.85; 95% confidence interval (95% CI), 1.37-2.51; CIMP-High, HR, 2.90; 95% CI, 1.53-5.49 compared with No-CIMP]. Within the high-level microsatellite instability group, no difference in survival was observed between the different CIMP groups. Our results show the interest of defining three subgroups of patients according to their methylation status (No-CIMP/CIMP-Low/CIMP-High). Methylation is an independent prognostic factor in MSS colon cancer.
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PMID:Hypermethylator phenotype in sporadic colon cancer: study on a population-based series of 582 cases. 1892 29

The MSH6 G39E germline polymorphism is not associated with an increased risk of either microsatellite stable or unstable sporadic colorectal cancer. Other than microsatellite instability, however, most genetic and epigenetic changes of tumors associated with this common variant have not been studied. The objective of our investigation was to evaluate associations between the MSH6 G39E (116G>A) polymorphism and CpG island methylator phenotype (CIMP) and BRAF V600E mutations in tumors from a sample of 1048 individuals with colon cancer and 1964 controls from Utah, Northern California, and Minnesota. The G39E polymorphism (rs1042821) was determined by the five prime nuclease assay. CIMP was determined by methylation-specific polymerase chain reaction (PCR) of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A. The BRAF V600E mutation was determined by sequencing exon 15. In microsatellite stable tumors, homozygous carriers of the G39E polymorphism had an increased risk of CIMP+ colon cancer (odds ratio (OR) 2.2, 95% confidence interval (CI) 1.1, 4.2) and BRAF V600E mutation (OR 3.1, 95% CI 1.01, 9.7) in a case-control comparison. This finding was not observed in unstable tumors; however, power may have been low to detect an association. Age at diagnosis, family history, and alcohol use did not interact with MSH6 G39E and CIMP. The MSH6 G39E germline polymorphism may be associated with CIMP+ colon cancer.
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PMID:MSH6 G39E polymorphism and CpG island methylator phenotype in colon cancer. 1958 61