Promoter methylation status and expression of O6-Methylguanine-DNA-Methyltransferase (MGMT) in pediatric brain germ cell tumors

• Main Authors: Chun-Hsiang Pai, 白竣翔
• Other Authors: Yann-Jang Chen
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/2p6h9w

碩士 === 國立陽明大學 === 生命科學暨基因體科學研究所 === 97 === Alkylating drugs such as temozolomide is used in the treatment of several human cancers, but the cytotoxicity of these anticancer drugs results from the alkylation of DNA is strongly attenuated by the repair ability of O6-methylguanine-DNA methyltransferase (MGMT). The cellular DNA repair protein MGMT, a DNA repair enzyme that removes the mutagenic alkyl-adducts from the O6-position of guanine and thereby causes resistance to alkylating agents. Aberrant methylation of CpG islands located in the promoter region of MGMT gene is associated with transcriptional inactivation of this DNA repair gene and result in low expression of the DNA repair enzyme. In some cancer cells, the expression of MGMT is silenced due to abnormal promoter methylation. Therefore, to realize the MGMT expression and its promoter methylation status is important for advancing benefit of these chemotherapy drugs in cancer patients. Brain germ cell tumor arises from the abnormal migration of germ cells which should be located on testis or ovarian in embryo development stage. Around half of these tumors occur in young people between 10 and 20 years old. The major treatments for brain germ cell tumors are radiation and Chemotherapy. In order to realize whether it is suitable to treat brain germ cell tumor patients with alkylating drugs, we performed immunohistochemistry (IHC), bisulfite methylation specific PCR (MSP) and bisulfite sequence on 21 pediatric brain germ cell tumors from Taipei Veterans General Hospital to investigate the relation between the expression of MGMT and the CpG methylation within their promoters in brain germ cell tumors. In our study, hypermethylation of MGMT was detected in five out of twenty-one (25%) cases in MSP. Sequence-1(CpG1~26) has the highest methylation frequency from 12 to 87% in each case, and the other regions are almost under 10%. In IHC, just one case lost the expression of MGMT, and the others had the different-grade expression of MGMT. The relation between MGMT expression and promoter methylation is not concordant. In addition to promoter methylation, some mechanisms may regulate the expression of MGMT, and this needs further evaluation.