Molecular genetic analysis and establishment of tailor-maid therapy for malignant brain tumors.

点击翻译按钮获取中文摘要

We have studied genetic alterations of several oncogenes and suppressor-oncogenes including TP53, INK4a/ARF, MDM2, BCL10, DcR3, and so on, in the point of clinical aspects. Resent development of nucleotide-array advanced the frontier of gene analyzes. In this research project, we investigated a series of 91 patients with malignant brain tumors including astrocytic tumors, intracranial germ cell tumors (ICGTs), and primary central nervous system lymphomas (PCNSLs) to determine genetic alterations of various genes. And we are going to make use of the obtained-results for establishing a tailor-made therapy based on array system. The following three results were obtained in this project term.1) Decoy receptor 3 (DcR3), negative regulator of Fas-mediated apoptosis, was amplified in 0 of 7 (0 %) low grade astrocytomas, 1 of 16 (6.3 %) anaplastic astrocytomas, and 7 of 34 (20.6 %) glioblastoma multiformes. These results suggest that the gene amplification is responsible for malignant features in high grade astrocytic tumors.2) While no inactivating mutations of BCL10 gene were found, many germinoma (5 of 10 germinoma : 50 %), had specific single nucleotide polymorphism (SNP) in exonl of BCL10. This SNP was found at significantly higher frequency in the Japanese population than in other population worldwide (p < 0.0001). The specific SNP in the BCL10 gene may be partly responsible for Japanese propensity of ICGTS.3) INK4a / ARF gene showed an alteration of homozygous deletion at a high frequency (9 of 14 : 64%) in patients with PCNSLs. The alteration was related with bcl-2 anti-apoptotic protein overexpression as well as shorter patient survival. This study suggeststhat the INK4a / ARF gene homozygous deletion and overexpression of the bcl-2 protein may serve as important predictors for prognosis of patients with PCNSLs.Making use of above mentioned results, we are going to check the accuracy of our gene-array system and develop it.