Department of General Surgery, University of Gothenburg, Sahlgrenska University Hospital/Ostra, Gothenburg, Sweden.
Mol Med. 2010 Sep-Oct;16(9-10):425-32. doi: 10.2119/molmed.2009.00156. Epub 2010 Jun 11.
We recently analyzed the hypermethylation status of the p16INK4a (p16) gene promoter in normal-appearing mucosa obtained from patients with colorectal cancer. Hypermethylation of p16 was associated with reduced survival of these patients. In the present study, germ line polymorphisms in the folate- and methyl-associated genes, methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR) and methionine synthase reductase (MTRR), were analyzed in the same patient cohort to find a possible link between these genetic variants and p16 hypermethylation. Genomic DNA was extracted from blood of patients (n = 181) and controls (n = 300). Genotype analyses were run on an ABI PRISM(®) 7900HT sequence-detection system (Applied Biosystems), using real-time polymerase chain reaction and TaqMan chemistry. The results showed that the genotype distributions of the patient and control groups were similar. No significant differences in cancer-specific or disease-free survival of stage I-III patients according to polymorphic variants were detected, nor were any differences in cancer-specific or disease-free survival detected when patients were subgrouped according to the MTHFR or MTR genotype groups and dichotomized by p16 hypermethylation status in mucosa. However, patients with the MTRR 66 AA/AG genotypes were found to have a significantly worse cancer-specific survival when the mucosa were positive, compared with negative, for p16 hypermethylation (hazard ratio 2.7; 95% confidence interval 1.2-6.4; P = 0.023). In contrast, there was no difference in survival among patients with the MTRR 66 GG genotype stratified by p16 hypermethylation status. These results indicate a relationship between genetic germ-line variants of the MTRR gene and p16 hypermethylation in mucosa, which may affect the clinical outcome of patients with colorectal cancer.
我们最近分析了来自结直肠癌患者的正常外观粘膜中 p16INK4a（p16）基因启动子的超甲基化状态。p16 的甲基化与这些患者的生存降低有关。在本研究中，分析了叶酸和甲基相关基因（亚甲基四氢叶酸还原酶（MTHFR）、蛋氨酸合成酶（MTR）和蛋氨酸合成酶还原酶（MTRR））中的种系多态性，以寻找这些遗传变异与 p16 超甲基化之间的可能联系。从患者（n = 181）和对照（n = 300）的血液中提取基因组 DNA。使用实时聚合酶链反应和 TaqMan 化学在 ABI PRISM（®）7900HT 序列检测系统（Applied Biosystems）上运行基因型分析。结果表明，患者和对照组的基因型分布相似。根据多态性变异，未检测到 I-III 期患者的癌症特异性或无病生存率存在显著差异，也未检测到根据 MTHFR 或 MTR 基因型组对患者进行亚组分析并根据粘膜中 p16 超甲基化状态进行二分类时的癌症特异性或无病生存率差异。然而，当粘膜 p16 超甲基化阳性时，MTRR66AA/AG 基因型的患者癌症特异性生存率明显较差，与阴性相比（危险比 2.7；95%置信区间 1.2-6.4；P = 0.023）。相比之下，根据 p16 超甲基化状态对 MTRR66GG 基因型的患者进行分层，其生存率没有差异。这些结果表明 MTRR 基因的遗传种系变异与粘膜中的 p16 超甲基化之间存在关系，这可能影响结直肠癌患者的临床结局。
