Nagasaka Takeshi, Sharp Gerald B, Notohara Kenji, Kambara Takeshi, Sasamoto Hiromi, Isozaki Hiroshi, MacPhee Donald G, Jass Jeremy R, Tanaka Noriaki, Matsubara Nagahide
Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
Clin Cancer Res. 2003 Nov 1;9(14):5306-12.
Because O(6)-methylguanine-DNA methyltransferase (MGMT) plays an essential role in repairing DNA damage caused by environmental alkylating chemicals, we were interested in determining whether we could see any obvious changes in the properties of colorectal cancers (CRCs) in which the MGMT gene had been silenced by hypermethylation and hence in which very few MGMT protein molecules were being produced.
We used a methylation-specific PCR assay to determine the methylation status of the MGMT promoter in the DNA molecules extracted from CRC and nontumor tissue samples from 116 patients who had undergone CRC surgery and for whom clinical outcome information was available on file.
We found evidence of MGMT promoter hypermethylation in 26 of 90 CRC cases, and we noted that the later the stage at which a tumor was diagnosed, the less likely its MGMT promoter was to be methylated (P = 0.03, adjusting for chemotherapy), especially for stage D patients (P = 0.01). We also found that CRC patients with unmethylated MGMT promoters were much more likely to experience recurrence within 36 months than patients with hypermethylated MGMT promoters (crude odds ratio, 14.0; 95% confidence interval, 2.42-81.01). After adjustment for stage, CRC patients with unmethylated MGMT promoters who had been exposed to chemotherapy were found to have a 5.3-fold greater risk of recurrence than those who had no exposure to chemotherapy (95% confidence interval, 1.15-30.92).
Hypermethylation of the MGMT promoter may be predictive of a low risk of recurrence in CRC patients receiving adjuvant chemotherapy.
由于O(6)-甲基鸟嘌呤-DNA甲基转移酶（MGMT）在修复环境烷基化化学物质引起的DNA损伤中起关键作用，我们感兴趣的是确定在MGMT基因因高甲基化而沉默且因此产生极少MGMT蛋白分子的结直肠癌（CRC）中，是否能观察到其性质的任何明显变化。
我们使用甲基化特异性PCR检测法来确定从116例接受CRC手术且有临床结局信息存档的患者的CRC和非肿瘤组织样本中提取的DNA分子中MGMT启动子的甲基化状态。
我们在90例CRC病例中的26例中发现了MGMT启动子高甲基化的证据，并且我们注意到肿瘤诊断阶段越晚，其MGMT启动子甲基化的可能性越小（P = 0.03，校正化疗因素），尤其是D期患者（P = 0.01）。我们还发现，MGMT启动子未甲基化的CRC患者在36个月内复发的可能性比MGMT启动子高甲基化的患者高得多（粗比值比，14.0；95%置信区间，2.42 - 81.01）。在校正分期后，发现接受化疗的MGMT启动子未甲基化的CRC患者复发风险比未接受化疗的患者高5.3倍（95%置信区间，1.15 - 30.92）。
MGMT启动子的高甲基化可能预示接受辅助化疗的CRC患者复发风险较低。
