甲基代谢酶和表观遗传调控因子的遗传变异：与结直肠癌启动子 CpG 岛过度甲基化的关联。
Genetic variants of methyl metabolizing enzymes and epigenetic regulators: associations with promoter CpG island hypermethylation in colorectal cancer.
机构信息
Departments of Epidemiology, GROW-School for Oncology and Developmental Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands.
出版信息
Cancer Epidemiol Biomarkers Prev. 2009 Nov;18(11):3086-96. doi: 10.1158/1055-9965.EPI-09-0289. Epub 2009 Oct 20.
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.
异常的 DNA 甲基化会影响结直肠癌的发生。叶酸代谢酶可能会影响甲基的生物利用度，而 DNA 和组蛋白甲基转移酶则参与基因表达的表观遗传调控。我们研究了叶酸代谢酶（MTHFR、MTR 和 MTRR）、DNA 甲基转移酶 DNMT3b 以及组蛋白甲基转移酶（EHMT1、EHMT2 和 PRDM2）的遗传变异与结直肠癌的关系，包括有无 CpG 岛甲基化表型（CIMP）、MLH1 甲基化过度和微卫星不稳定性。在荷兰饮食与癌症队列研究中，659 例病例和 1736 例亚队列成员（n = 120852）进行了病例-队列分析，以常见纯合子作为参照，计算发病率比值。男性 MTHFR 677TT 基因型结直肠癌风险降低（发病率比值，0.49；P = 0.01），但 T 等位基因与女性风险增加相关（发病率比值，1.39；P = 0.02）。MTR 2756GG 基因型与结直肠癌风险增加相关（发病率比值，1.58；P = 0.04），而女性携带 DNMT3b C-->T（rs406193；发病率比值，0.72；P = 0.04）或 EHMT2 G-->A（rs535586；发病率比值，0.76；P = 0.05）多态性时则呈相反关系。尽管存在显著相关性（P < 0.001），但只有 41.5%和 33.3%的 CIMP 肿瘤分别存在 MLH1 甲基化过度和微卫星不稳定。我们观察到男性中 MTR A2756G 与 CIMP 之间呈负相关（发病率比值，0.58；P = 0.04），女性中 MTRR A66G 与 MLH1 甲基化过度之间呈负相关（发病率比值，0.55；P = 0.02）。总之，MTHFR、MTR、DNMT3b 和 EHMT2 多态性与结直肠癌相关，而 MTR 和 MTRR 的罕见变异可能会降低启动子的过度甲基化。CIMP、MLH1 甲基化过度和微卫星不稳定之间的不完全重叠表明这些相关的“甲基化表型”可能并不相似，应该分别进行研究。
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