Silber J R, Blank A, Bobola M S, Mueller B A, Kolstoe D D, Ojemann G A, Berger M S
Department of Neurological Surgery, University of Washington, Seattle, WA 98195, USA.
Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):6941-6. doi: 10.1073/pnas.93.14.6941.
Exposure to exogenous alkylating agents, particularly N-nitroso compounds, has been associated with increased incidence of primary human brain tumors, while intrinsic risk factors are currently unknown. The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is a major defense against the carcinogenicity of N-nitroso compounds and other alkylators. We report here that in 55% (64/117) of cases, histologically normal brain tissue adjacent to primary human brain tumors lacked detectable MGMT activity [methyl excision repair-defective (Mer-) status]. The incidence of Mer- status in normal brain tissue from brain tumor patients was age-dependent, increasing from 21% in children 0.25-19 years of age to 75% in adults over 50. In contrast, Mer- status was found in 12% (5/43) of normal brain specimens from patients operated for conditions other than primary brain tumors and was not age-dependent. The 4.6-fold elevation in incidence of Mer- status in brain tumor patients is highly significant (chi2 = 24; p < or = 0.001). MGMT activity was independent of age in the lymphocytes of brain tumor patients and was present in lymphocytes from six of nine tumor patients whose normal brain specimen was Mer-. DNA polymerase beta, apurinic/apyrimidinic endonuclease, and lactate dehydrogenase activities were present in all specimens tested, including Mer- specimens from brain tumor patients. Our data are consistent with a model of carcinogenesis in human brain in which epigenetically regulated lack of MGMT is a predisposing factor and alkylation-related mutagenesis is a driving force.
接触外源性烷化剂，尤其是N-亚硝基化合物，与原发性人脑肿瘤发病率增加有关，而内在风险因素目前尚不清楚。DNA修复蛋白O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）是抵御N-亚硝基化合物和其他烷化剂致癌性的主要防御机制。我们在此报告，在55%（64/117）的病例中，原发性人脑肿瘤附近的组织学正常脑组织缺乏可检测到的MGMT活性[甲基切除修复缺陷（Mer-）状态]。脑肿瘤患者正常脑组织中Mer-状态的发生率与年龄有关，从0.25 - 19岁儿童中的21%增加到50岁以上成年人中的75%。相比之下，在因原发性脑肿瘤以外的疾病接受手术的患者的正常脑标本中，12%（5/43）发现了Mer-状态，且与年龄无关。脑肿瘤患者中Mer-状态发生率升高4.6倍具有高度显著性（χ2 = 24；p≤0.001）。MGMT活性在脑肿瘤患者的淋巴细胞中与年龄无关，并且在9名肿瘤患者中有6名的淋巴细胞中存在MGMT活性，其正常脑标本为Mer-。DNA聚合酶β、脱嘌呤/脱嘧啶内切酶和乳酸脱氢酶活性在所有测试标本中均存在，包括脑肿瘤患者的Mer-标本。我们的数据与人类脑癌发生模型一致，在该模型中，表观遗传调控导致的MGMT缺乏是一个易感因素，而烷基化相关的诱变是驱动力。
