de Vogel Stefan, Bongaerts Brenda W C, Wouters Kim A D, Kester Arnold D M, Schouten Leo J, de Goeij Anton F P M, de Bruïne Adriaan P, Goldbohm R Alexandra, van den Brandt Piet A, van Engeland Manon, Weijenberg Matty P
Department of Epidemiology, GROW, School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.
Carcinogenesis. 2008 Sep;29(9):1765-73. doi: 10.1093/carcin/bgn074. Epub 2008 Mar 13.
Intake of dietary factors that serve as methyl group donors may influence promoter hypermethylation in colorectal carcinogenesis. We investigated whether dietary folate, vitamin B2 and vitamin B6, methionine and alcohol were associated with mutL homologue 1 (MLH1) hypermethylation and the related molecular phenotypes of MLH1 protein expression, microsatellite instability (MSI) and BRAF mutations in patients with colorectal carcinomas. Within the Netherlands Cohort Study on diet and cancer (n = 120 852), 648 cases (367 men and 281 women) and 4059 subcohort members were available for data analyses from a follow-up period between 2.3 and 7.3 years after baseline. Gender-specific adjusted incidence rate ratios (RRs) were calculated over categories of dietary intake in case-cohort analyses. The intakes of folate, vitamin B2, methionine and alcohol were not associated with risk of tumors showing MLH1 hypermethylation, those lacking MLH1 protein expression or with MSI. Among men, we observed strong positive associations between folate and BRAF-mutated tumors (RR = 3.04 for the highest versus lowest tertile of intake, P(trend) = 0.03) and between vitamin B6 and tumors showing MLH1 hypermethylation (highest versus lowest tertile: RR = 3.23, P(trend) = 0.03). Among women, the relative risks of tumors with BRAF mutations or MLH1 hypermethylation were also increased in the highest tertiles of folate and vitamin B6 intake, respectively, but these did not reach statistical significance. The positive associations between folate intake and tumors harboring BRAF mutations and between vitamin B6 intake and those showing MLH1 hypermethylation were most pronounced among men and may suggest that these vitamins enhance colorectal cancer risk through genetic as well as epigenetic aberrations.
作为甲基供体的膳食因素的摄入可能会影响结直肠癌发生过程中的启动子高甲基化。我们调查了膳食叶酸、维生素B2、维生素B6、蛋氨酸和酒精是否与结直肠癌患者的mutL同源物1（MLH1）高甲基化以及MLH1蛋白表达、微卫星不稳定性（MSI）和BRAF突变的相关分子表型有关。在荷兰饮食与癌症队列研究（n = 120852）中，有648例患者（367名男性和281名女性）以及4059名亚队列成员可用于数据分析，这些数据来自基线后2.3至7.3年的随访期。在病例队列分析中，计算了按膳食摄入量类别调整的性别特异性发病率比（RRs）。叶酸、维生素B2、蛋氨酸和酒精的摄入量与显示MLH1高甲基化的肿瘤风险、缺乏MLH1蛋白表达的肿瘤风险或MSI均无关。在男性中，我们观察到叶酸与BRAF突变肿瘤之间存在强正相关（摄入量最高三分位数与最低三分位数相比，RR = 3.04，P（趋势）= 0.03），维生素B6与显示MLH1高甲基化的肿瘤之间存在强正相关（最高三分位数与最低三分位数相比：RR = 3.23，P（趋势）= 0.03）。在女性中，叶酸和维生素B6摄入量最高三分位数时，BRAF突变或MLH1高甲基化肿瘤的相对风险也分别增加，但未达到统计学意义。叶酸摄入量与携带BRAF突变的肿瘤之间以及维生素B6摄入量与显示MLH1高甲基化的肿瘤之间的正相关在男性中最为明显，这可能表明这些维生素通过基因及表观遗传异常增加了结直肠癌风险。
