Brüstle O, Ohgaki H, Schmitt H P, Walter G F, Ostertag H, Kleihues P
Laboratory of Neuropathology, Institute of Pathology, University of Zürich, Switzerland.
Cancer. 1992 May 1;69(9):2385-92. doi: 10.1002/1097-0142(19920501)69:9<2385::aid-cncr2820690929>3.0.co;2-3.
Three patients had supratentorial malignant brain tumors 7 to 9 years after prophylactic central nervous system (CNS) treatment for acute lymphocytic leukemia or malignant T-cell lymphoma. Therapy was administered at the age of 3 to 8 years and included cranial irradiation (total dose, 1800 to 2400 cGy) and intrathecal methotrexate. The brain tumors had histologic and immunohistochemical features of primitive neuroectodermal tumors (PNET), including neuroblastic rosettes, rhythmic arrangement of tumor cells, and immunohistochemical expression of glial, and in one patient neuronal, marker proteins. Using polymerase chain reaction-mediated DNA amplification from paraffin-embedded tissues and subsequent DNA sequence analysis, an activating point mutation was detected in the K-ras protooncogene in one tumor. This mutation was a G to A transition in position 2 of codon 12, substituting aspartate (GAT) for glycine (GGT). This type of mutation has not been observed before in human brain tumors, but it is frequent in radiation-induced murine lymphomas. These observations suggest that PNET can be induced after completion of the embryonal and fetal development of the human CNS. Oncogene-activating point mutations may represent a pathogenetic mechanism involved in the genesis of radiation-induced brain tumors.
3例患者在接受急性淋巴细胞白血病或恶性T细胞淋巴瘤预防性中枢神经系统（CNS）治疗7至9年后发生幕上恶性脑肿瘤。治疗在3至8岁时进行，包括颅脑照射（总剂量1800至2400 cGy）和鞘内注射甲氨蝶呤。脑肿瘤具有原始神经外胚层肿瘤（PNET）的组织学和免疫组化特征，包括神经母细胞性菊形团、肿瘤细胞的节律性排列以及胶质标志物蛋白的免疫组化表达，在1例患者中还有神经元标志物蛋白的表达。通过聚合酶链反应介导的石蜡包埋组织DNA扩增及随后的DNA序列分析，在1例肿瘤的K-ras原癌基因中检测到一个激活点突变。该突变是密码子12第2位的G到A转换，将甘氨酸（GGT）替换为天冬氨酸（GAT）。这种类型的突变在人类脑肿瘤中此前未见报道，但在辐射诱导的小鼠淋巴瘤中很常见。这些观察结果提示，PNET可在人类CNS胚胎和胎儿发育完成后诱发。癌基因激活点突变可能是辐射诱导脑肿瘤发生的一种致病机制。
