Abstract 1808: Gene expression signature of malignant astrocytomas and its association with MGMT promoter methylation status.

Abstract

Abstract Background: MGMT promoter methylation has been reported as a predictive marker, not only for response to temozolomide (TMZ), but also for the longer survival of the patients with malignant astrocytomas (MAs) regardless of treatment with TMZ. This led us to hypothesize that methylation status of MGMT in MAs could somehow associate with epigenetic modification of other cancer-related gene promoters resulting in alterations of gene expression profiles and acquisition of therapy- sensitive characters. In this study, to elucidate the molecular characteristics that contribute to chemosensitivity and prognosis in MAs, we conducted gene expression profiling of the tumors with or without MGMT promoter methylation. Materials and Methods: Forty-seven MAs including 5 anaplastic astrocytomas and 42 glioblastomas were enrolled in this study. Methylation status of MGMT gene promoter was evaluated by methylation-specific PCR and subsequent pyrosequencing. Gene expression profile was analyzed using 13,000 genes-cDNA microarray which was developed in our institute. Differentially expressed genes between MGMT-methylated and -unmethylated cases were picked up by statistical analysis (Wilcoxon test). Results: MGMT promoter methylation was found in 26 out of 47 cases. Among the 13,000 genes examined, 163 genes demonstrated statistically significant difference in expression between MGMT-methylated and -unmethylated cases. 22 genes demonstrated lower expression in MGMT-methylated cases, while the remaining 141 genes showed higher expression in methylated cases. When we classify the cases into two groups according to the expression profiles of these 163 genes, survival of the patients were clearly divided (median survival: 18.9m vs. 9.7m, p=0.039). Annotation analysis indicated that the 22 genes with lower expression in MGMT-methylated tumors include those which actively participate in tumor progression, invasion and metastasis, and one of these showed a significant prognostic power in 47 MAs examined (p=0.049). Validation of methylation status of these gene promoters is underway. Conclusion: We identified a gene expression signature strongly correlated with MGMT methylation in MAs, which might contribute to predict chemosensitivity of tumors as well as prognosis of the patients with MA in combination of MGMT methylation. Citation Format: Toshihiko Iuchi, Miki Ohira, Sana Yokoi, Hajime Kageyama, Yuzo Hasegawa, Koichiro Kawasaki, Tsukasa Sakaida, Akira Nakagawara. Gene expression signature of malignant astrocytomas and its association with MGMT promoter methylation status. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1808. doi:10.1158/1538-7445.AM2013-1808