EPIG-07: PROGNOSTIC ROLE OF HISTONE H3 LYSINE 27 DEMETHYLASE (UTX) AND HISTONE H3 LYSINE 4 METHYLTRANSFERASE (MLL4) ON THE GLIOBLASTOMA PATIENTS WITH METHYLATED MGMT PROMOTER

OBJECTIVE: This study was undertaken primarily to investigate the epigenetic and prognostic role of H3K4 methyltransferase (MLL4) and H3K27 demethylase (UTX) in PFS and OS of glioblastoma patients who were treated with radiotherapy and/or chemotherapy after surgical resection. METHODS: The medical records of 76 patients with glioblastoma newly diagnosed and histologically proven from January 2002 to December 2013 at our hospital were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues obtained by surgical resection for MLL4 and UTX. The methylation status of MGMT promoter was determined retrospectively by MS-PCR analysis. RESULTS: During follow-up period (mean duration of 27.5 months, ranged from 4.1 to 43.5 months), 68 patients (89.5%) died. MGMT promoter was methylated in 49 patients (64.5%) and unmethylated in 27 (35.5%). In terms of immunoreactivity of UTX-MLL4 complex, overexpression was found in 42 samples (55.3%) and underexpression in 34 samples (44.7%). Median PFS was 9.2 months (95% confidence interval [CI] of 6.8-11.6 months). Extent of surgery and methylation status of MGMT promoter was associated with PFS in multivariate analysis of factors predicting PFS. Median OS was 18.6 months (95% CI of 16.3-20.9 months). Age of patients (p = 0.004), performance status (p < 0.05), extent of surgery (p < 0.05), RPA class (p < 0.05), methylation status of MGMT promoter (p = 0.010), and immunoreactivity of UTX-MLL4 complex (p = 0.001) were associated with OS in multivariate analysis of factors predicting OS. Interestingly, in the patients with unmethylated MGMT promoter, immunoreactivity of UTX-MLL4 complex was not associated with OS (p = 0.350). However, in the patients with methylated MGMT promoter, immunoreactivity was strongly associated with OS (p < 0.001). Even patients with underexpression of UTX-MLL4 complex did not have statistical difference in OS between methylated MGMT promoter (p = 0.589) and unmethylated MGMT promoter (p = 0.838). CONCLUSION: This study suggests that overexpression of UTX-MLL4 complex should influence on the better outcome of glioblastoma patients with methylated MGMT promoter.