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From the Departments of Radiation Oncology,* Pathology, and Neurosurgery, and the Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia
TMS1/ASC is an intracellular signaling molecule with proposed roles in the regulation of apoptosis, nuclear factor-
B activation, and cytokine maturation. Previous studies have shown that TMS1/ASC is silenced by epigenetic means in human breast tumors. In this study, we examined methylation and expression of TMS1/ASC in glioblastoma multiforme (GBM). Whereas normal brain tissue was unmethylated at the TMS1 locus and expressed TMS1 message, 11 of 23 human GBM cell lines exhibited reduced or absent expression of TMS1 that was associated with aberrant methylation of a CpG island in the promoter of the TMS1 gene. Quantitative analysis showed that there was an inverse correlation between the degree of methylation and level of TMS1 expression. Treatment of GBM cell lines lacking TMS1 expression with the methyltransferase inhibitor 5-aza-2'deoxycytidine resulted in partial demethylation and re-expression of TMS1. Analysis of primary tissues indicated that the TMS1 gene is unmethylated and expressed in normal brain, where its expression is restricted to astrocytes. In contrast, TMS1 was aberrantly methylated in 43% (10 of 23) primary GBM specimens. Tumors that exhibited aberrant methylation of TMS1 generally expressed reduced or absent expression of TMS1 as compared to unmethylated cases. Methylation of TMS1 was not associated with patient age, gender, or treatment status. Although the relationship did not reach statistical significance, there was a trend toward increased overall survival for patients with unmethylated tumors. For one patient, disease progression from astrocytic astrocytoma (World Health Organization grade III) to GBM (World Health Organization grade IV) was associated with selective expansion of TMS1-negative cells. The data suggest a role for the epigenetic silencing of TMS1 in the pathogenesis of human GBM. Methylation of TMS1 may prove to be a useful prognostic marker and/or predictor of patient survival and tumor malignancy.
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