RESUMO
Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C-->T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G-->A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related "methylation phenotypes" may not be similar and should be investigated separately.
Assuntos
Neoplasias Colorretais/genética , Ilhas de CpG/genética , Metilação de DNA , Epigênese Genética , Proteínas de Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Regiões Promotoras Genéticas/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , Neoplasias Colorretais/diagnóstico , DNA (Citosina-5-)-Metiltransferases/genética , Feminino , Genótipo , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Humanos , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL , Estadiamento de Neoplasias , Países Baixos , Proteínas Nucleares/genética , Prognóstico , Estudos Prospectivos , Fatores de Risco , Canais de Cátion TRPM/genética , DNA Metiltransferase 3BRESUMO
An association between high intake of folate and reduced risk of cancer has been suggested by previous research. However, epidemiologic data from cohort studies regarding the relationship between dietary folate and pancreatic cancer are sparse and inconsistent. We examined the association between dietary folate intake and risk of pancreatic cancer within the Netherlands Cohort Study on diet and cancer. Men and women (120,852), ages 55 to 69 years, were recruited. Information on diet was collected at baseline by means of food frequency questionnaires, and the cohort was followed for 13.3 years. Total folate and vitamer intake were calculated using folate contents of food items derived from a validated liquid chromatography trienzyme method. Cases (n = 363) were identified by record linkage with regional cancer registries and the Dutch National Database of Pathology Reports. A case-cohort approach was used using the follow-up data of a random subcohort (n = 5,000) identified at the onset of the cohort. Multivariable hazard ratios with 95% confidence intervals were estimated using Cox proportional hazards model. After adjusting for age, gender, smoking status, number of years smoked, number of cigarettes smoked per day, and intake of added sugar multivariate hazard ratio comparing the highest and lowest quintiles of folate intake for pancreatic cancer risk was 1.37 (confidence interval, 0.97-1.94; P(trend) = 0.07). When folate vitamers were analyzed separately, results did not show a difference in association. Our results do not support a protective association of total dietary folate or individual folate vitamers on the risk of pancreatic cancer.