Background: An altered pattern of epigenetic modifications is central to the development and progression of various tumors. We studied epigenetic changes involving multiple modifications of histones to better predict prognosis of glioma patients.Methods: Immunohistochemistry was done to investigate global histone modification expression of histone 3 lysine 4 dimethylation (H3K4diMe), histone 4 arginine 3 monomethylation (H4R3monoMe), histone 4 lysine 20 trimethylation (H4K20triMe), and acetylation of histone 3 lysine 9 (H3K9Ac), histone 3 lysine 18 (H3K18Ac), histone 4 lysine 12 (H4K12Ac), and histone 4 lysine 16 (H4K16Ac) in resected tumor samples of 230 glioma patients. Data were analyzed using a recursive partitioning analysis (RPA).Results: RPA classified the patients into 10 distinct prognostic groups based on WHO grade, histology, and histone modifications: H3K9Ac (<88% or ≥88% tumor cells), H3K4diMe (<64% or ≥64% tumor cells), H3K18Ac (<74% or ≥74% tumor cells), and H4K20triMe (<75% or ≥75% tumor cells). The 10 groups were associated with significantly different progression-free (P < 0.0001) and overall survival (P < 0.0001). Cox proportional hazards models including age, sex, WHO grade, histology, extent of tumor resection, Karnofsky performance status score, and RPA groups retained age and RPA groups as the sole independent factors significantly influencing overall survival. For progression-free survival, RPA grouping was the only independent prognostic factor.Conclusions: Multiple histone modifications seem to have prognostic relevance in glioma. Impact: Further evaluation of histone modifications as prognostic markers of treatment and predictors of chemotherapy response using histone deacetylase inhibitors is warranted. Cancer Epidemiol Biomarkers Prev;

BackgroundFRAT1 positively regulates the Wnt/β-catenin signaling pathway by inhibiting GSK-3-mediated phosphorylation of β-catenin. It was originally characterized as a protein frequently rearranged in advanced T cell lymphoma, but has recently also been identified as a proto-oncogene involved in tumorigenesis. Our previous studies showed that FRAT1 was dramatically overexpressed in gliomas and its expression level was significantly increased along with clinicopathological grades.MethodsIn the current study, we used RT-PCR and Western blotting to assess the mRNA and protein levels of FRAT1 in three glioma cell lines. In addition, to evaluate its functional role in gliomas, we examined the effects of FRAT1 knockdown on proliferation, migration and invasion in vitro and tumor growth in vivo using glioblastoma U251 cells and RNAi.ResultsFRAT1 was highly expressed in all three glioma cell lines. RNAi-mediated down-regulation of endogenous FRAT1 in human glioblastoma U251 cells resulted in suppression of cell proliferation, arrest of cell cycle, inhibition of cell migration and invasion in vitro. Moreover, FRAT1 depletion significantly impaired tumor xenograft growth in nude mice.ConclusionsOur results highlight the potential role of FRAT1 in tumorigenesis and progression of glioblastoma. These findings provide a biological basis for FRAT1 as a potential molecular marker for improved pathological grading and as a novel candidate therapeutic target for glioblastoma management.

Temozolomide (TMZ) alone has been proposed as a promising alternative to radiotherapy (RT) in elderly glioblastoma (GBM) patients. We report a meta-analysis to systematically evaluate TMZ monotherapy in older GBM patients. A systematic literature search was performed using PubMed, EMBASE and the Cochrane database. Studies comparing TMZ versus RT in elderly patients (≥ 65 years) with newly diagnosed GBM were eligible for inclusion. Two randomized clinical trials (RCTs) and three comparative studies were included in the analyses, which revealed an overall survival (OS) advantage for TMZ compared with RT (HR [hazard ratio] 0.86, 95 % CI [confidence interval] 0.74-1.00). However, a sensitivity analysis of 2 RCTs only supported its non-inferiority (HR 0.91, 95 % CI 0.66-1.27). Most elderly patients tolerated TMZ despite an increased risk of grade 3-4 (G3-4) toxicities, especially hematological toxicities. The quality of life was similar between the groups. In the MGMT analysis, methylated tumors were associated with a longer OS than unmethylated tumors among elderly patients receiving TMZ monotherapy (HR 0.50, 95 % CI 0.35-0.70). Moreover, in patients with methylated tumors, TMZ was more beneficial than RT alone in improving OS (TMZ vs. RT: HR 0.66, 95 % CI 0.47-0.93) whereas the opposite was true for those with unmethylated tumors (HR 1.32, 95 % CI 1.00-1.76). Although the meta-analysis demonstrated the non-inferiority to RT in improving OS, TMZ alone was not a straightforward solution for elderly GBM patients because of an increased risk of G3-4 toxicities, especially hematological toxicities. MGMT testing might be helpful for determining individualized treatment.