In this study, we analyzed the prognostic value of epithelial membrane protein 3 (EMP3) in terms of overall survival (OS) in glioblastoma multiforme (GBM) and the association between its expression and DNA methylation.Bioinformatic analysis was performed by using data from the Cancer Genome Atlas (TCGA) database.EMP3 expression was markedly higher in GBM tissues than in normal brain tissues. High EMP3 expression was associated with significantly worse OS in patients with GBM. Univariate and multivariate analysis showed that EMP3 expression was an independent prognostic factor of poor OS no matter converting its expression into categorical variables (Hazard Ratio [HR] = 1.359, 95%CI: 1.118–1.652, P = .002) or setting it as a continuous variable (HR = 1.178, 95%CI: 1.101–1.260, P < .001). Among different subtypes of GBM, proneural subtype had the lowest EMP3 expression. The lowest EMP3 expression was observed in cluster 5 DNA methylation, which all belong to G-CIMP phenotype. Regression analysis confirmed a moderate negative correlation between EMP3 expression and its DNA methylation (Pearson's r = −0.61).Based on these findings, we infer that high EMP3 expression might be an independent indicator of unfavorable OS in GBM. EMP3 expression might be repressed by DNA methylation.
Our laboratory is interested in defining molecular pathways that help distinguish various histotypes of endometrial cancer. Type 1 endometrial cancer (low grade endometrioid adenocarcinoma) is characterized by superficial myometrial invasion, low clinical stage, and excellent prognosis. Type 2 endometrial cancer (grade 3 endometrioid adenocarcinoma, uterine papillary serous carcinoma, and malignant mixed mullerian tumor) is associated with deep myometrial invasion, metastasis, advanced clinical stage, and poor prognosis. One approach that we have used to define the molecular characteristics of these endometrial tumors is to analyze CpG island methylation patterns. Gene methylation is an important mechanism of tumor suppressor gene inactivation in a wide variety of neoplasms. We have modified existing techniques for methylation‐specific PCR for effective use in formalin‐fixed, paraffin‐embedded tissues. To date, we have analyzed a large series (greater than 100) different endometrial tumors for gene methylation patterns, using a panel of 12 different genes. A subset of the data for endometrioid tumors and uterine MMMT will be presented at the symposium. The endometrioid and MMMT groups have similar percentages of tumors with a methylator phenotype (tumor with two or more genes methylated). However, the pattern of gene methylation was distinct for several genes. Similar to previous studies, we found methylation of MLH1 and resulting microsatellite instability to be extremely uncommon in uterine MMMT compared to endometrioid adenocarcinoma. Methylation of MINT 31, a common event in endometrioid tumors, is also significantly less common in MMMT. Several important genes showed similar methylation frequencies in the endometrioid and MMMT groups. These include apoptosis‐promoting genes (DAP‐K and RASSF1) and cell cycle regulatory genes (p14 and p16). RASSF1, which encodes a pro‐apoptotic protein downstream from RAS, is methylated in a majority of the endometrioid tumors and MMMT. These results are intriguing, especially considering that the established frequency of RAS mutation in endometrial cancer is relatively low (12–25% of cases). It has been proposed by several different groups that RAS mutation and methylation of RASSF1 may be mutually exclusive events. Our preliminary findings for endometrial cancer certainly support this assertion. Finally, analysis of COX‐2 methylation has yielded exciting results. Previously, it had been proposed that induction of COX‐2 leads to PGE2 synthesis, which causes induction of aromatase. Increased aromatase levels contribute to increased local production of estrogens, which contributes to tumor cell growth. Therefore, we were surprised to find that nearly half of the endometrioid tumors and MMMT demonstrated methylation of COX‐2. Since gene methylation usually implies decreased gene expression, these findings did not support the “COX‐2/aromatase/estrogen” pathway in endometrial cancer. Quantitative PCR and immunohistochemistry supported these findings. Collectively, these results su...
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