Molecular genetic alterations in radiation-induced astrocytomas

Astrocytic tumors occasionally arise in the central nervous system followin g radiotherapy. It is not clear if these gliomas represent a unique molecul ar genetic subset. We identified nine cases in which an astrocytoma arose w ithin ports of previous radiation therapy, with total doses ranging from 24 00 to 5500 cGy, Irradiated primary lesions included craniopharyngioma, pitu itary adenoma, Hodgkin's lymphoma, ependymoma, pineal neoplasm, rhabdomyosa rcoma, and three cases of lymphoblastic malignancies, Patients ranged from 9 to 60 years of age and developed secondary tumors 5 to 23 years after rad iotherapy. The 9 postradiation neoplasms presented as either anaplastic ast rocytoma (3 cases) or glioblastoma multiforme (6 cases),Two of the latter c ontained malignant mesenchymal components. We performed DNA sequence analys is, differential polymerase chain reaction (PCR), and quantitative PCR on D NA from formalin-fixed, paraffin-embedded tumors to evaluate possible alter ations of p53, PTEN, K-ras, EGFR, MTAP, and p16 (MTS1/CDKN2) genes. By quan titative PCR, we found EGFR gene amplification in 2 of 8 tumors. One of the se demonstrated strong immunoreactivity for EGFR, Quantitative PCR showed c hromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7), Five of 9 tumors demonstrated diffuse nuclear immun oreactivity for p53 protein. Sequencing of the p53 gene in these 9 cases re vealed a mutation in only one of these cases, a G-to-A substitution in codo n 285 (exon 8), Somewhat unexpectedly, no mutations were identified in PTEN , a commonly altered tumor suppressor gene in ne novo glioblastoma multifor mes, Unlike some radiation-induced tumors, no activating point mutations of the K-ras proto-oncogene or base pair deletions of tumor suppressor genes were noted. These radiation-induced tumors are distinctive in their high hi stological grade at clinical presentation. The spectrum of molecular geneti c alterations appears to be similar to that described in spontaneous high g rade astrocytomas, especially those of the de novo type.