Abstract 5264: Are the methylation of MGMT (O6-methylguanine-DNA methyltransferase) and the DNA mismatch repair (MMR) mechanism frequently involved in pediatric cancers?

Abstract

Abstract In pediatric oncology more and more protocols are including now temozolomide (TMZ) as a drug in the first line treatment or at relapse time. MGMT activity is known to circumvent the toxicity of alkylating agents such as TMZ. The defect of MMR mechanism is involved also as a cellular way for cancers to resist to TMZ. Only few studies have been already done in the pediatric field focusing on the study of these markers of TMZ resistance. Based on the new therapeutic indications of this drug in pediatric cancers, we performed a study in 100 malignant pediatric tumors from various origins to evaluate the MGMT methylation and the MMR mechanism. Material and methods: 12 high grade gliomas (HGG), 13 medulloblastomas (MB), 15 osteosarcomas (OS), 15 Ewing sarcomas (EWS), 15 rhabdomyosarcomas (RMS), 15 NBs and 15 acute lymphoblastic leukemias (ALLs) were included retrospectively in the study. DNA was extracted from tumors at diagnosis. In all tumors, the methylated status of MGMT was analyzed by methylation specific PCR (MS-PCR). Simultaneously, its expression was studied by immunohistochemistry. To analyze the MMR status in each tumor, an allelotyping method was performed in these tumors by using the NIH recommended microsatellites. Results: Out of these 100 samples, 3 tumors (2 HGGs and 1 MB) were presenting a MSI (microsatellite instability), witness of a MMR deficiency. Only 5 tumors (2 EWSs, 2 HGGs and 1 MB) had a methylated MGMT promoter. One HGG was presenting both abnormalities at the same time. The immunohistochemical results were concordant with MS-PCR observations. Concerning the tumors treated with TMZ (12 HGGs, 4 MBs, 2 EWSs and 4 NBs), we do not observed any differences on survival between the unmethylated and methylated tumors. Discussion: Methylation of MGMT promoter and MMR deficiency are rare in pediatric tumors and therefore seem not to be the major mechanisms involved in the sensitivity to TMZ. Our results suggest that in pediatric tumors, other mechanisms for TMZ sensitivity or resistance should be activated. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5264.