Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents
Human colorectal mucosal O6-alkylguanine DNA-alkyltransferase activity and DNA-N7-methylguanine levels in colorectal adenoma cases and matched referents
复制标题
DOI：
10.1136/gut.2006.097899
复制
发表时间：
2007-03-01
期刊：
影响因子：
24.5
通讯作者：
Povey, A. C.
中科院分区：
文献类型：
--
作者：
Lees, N. P.;Harrison, K. L.;Povey, A. C.
背景和目标：O-6-烷基鸟嘌呤 DNA 烷基转移酶 (MGMT) 提供针对烷化剂诱导的 GCRAT 转变突变的保护。此类突变常见于大型结直肠腺瘤的 KRAS 癌基因中，但人类腺瘤或突变风险是否受到 MGMT 活性和烷化剂暴露的影响尚不清楚。因此，在患有和不患有腺瘤的患者的正常组织中测定了MGMT活性以及作为烷化剂暴露指标的DNA-N7-甲基鸟嘌呤（N7-MeG）水平。方法：在结肠镜检查过程中，从85名经组织学证实的结直肠腺瘤患者（病例）和85名年龄、性别和活检部位相匹配的无胃肠道肿瘤患者（参考对象）中收集正常结直肠粘膜活检标本。分别测量结直肠组织提取物和 DNA 中的 MGMT 活性和 N7-MeG 水平。结果：病例正常粘膜中的 MGMT 活性高于参考对象（6.65 +/- 3.03 vs 5.61 +/- 2.74 fmol/mu g DNA，p = 0.01）。在对病例进行分层时，发现大腺瘤病例正常粘膜中的 MGMT 活性相当高 (p = 0.003)，而 K-ras 基因中存在 GC -> AT 转换突变的病例中 MGMT 活性稍高 (p = 0.03)。 MGMT 水平升高与腺瘤风险增加相关（每单位活动增加 OR 1.17，95% CI 1.03 至 1.33）。在 89% 的病例和 93% 的参考对象的 DNA 中发现了可检测水平的 N7-MeG，水平范围为 < 0.1 至 7.7 mu mol/mol dG。病例和参考对象具有相似的 DNA-N7-MeG 水平。结论：人类普遍接触甲基化剂。腺瘤患者正常粘膜中的 MGMT 活性增加。
Background and aims: O-6-alkylguanine DNA-alkyltransferase (MGMT) provides protection against alkylating agent-induced GCRAT transition mutations. Such mutations are frequently seen in the KRAS oncogene of large colorectal adenomas, but whether adenoma or mutational risk in humans is influenced by MGMT activity and alkylating agent exposure is unclear. Hence, MGMT activity and, as an indicator of alkylating agent exposure, DNA-N7-methylguanine (N7-MeG) levels were determined in the normal tissue of patients with and without adenomas.Methods: Biopsy specimens of normal colorectal mucosa were collected during colonoscopy from 85 patients with histologically proved colorectal adenomas ( cases) and from 85 patients free of gastrointestinal neoplasia ( referents) matched by age, sex and biopsy location. MGMT activity and N7-MeG levels were measured in colorectal tissue extracts and DNA, respectively.Results: MGMT activity was higher in the normal mucosa of cases than in referents (6.65 +/- 3.03 vs 5.61 +/- 2.74 fmol/mu g DNA, p = 0.01). On stratification of cases, MGMT activity was found to be considerably greater in the normal mucosa of cases with large adenomas ( p = 0.003) and slightly higher in cases with a GC -> AT transition mutation in the K-ras gene ( p = 0.03). Elevated MGMT levels were associated with an increased risk of adenoma ( OR 1.17, 95% CI 1.03 to 1.33 per unit increase in activity). Detectable levels of N7-MeG were found in DNA from 89% of cases and 93% of referents, with levels ranging from < 0.1 to 7.7 mu mol/mol dG. Cases and referents had similar DNA-N7-MeG levels.Conclusions: Human exposure to methylating agents is widespread. MGMT activity is increased in the normal mucosa of patients with adenomas.