Expression Analysis of Genes Involved in the RB/E2F Pathway in Astrocytic Tumors.

Astrocytic gliomas, which are derived from glial cells, are considered the most common primary neoplasias of the central nervous system (CNS) and are histologically classified as low grade (I and II) or high grade (III and IV). Recent studies have shown that astrocytoma formation is the result of the deregulation of several pathways, including the RB/E2F pathway, which is commonly deregulated in various human cancers via genetic or epigenetic mechanisms. On the basis of the assumption that the study of the mechanisms controlling the INK4/ARF locus can help elucidate the molecular pathogenesis of astrocytic tumors, identify diagnostic and prognostic markers, and help select appropriate clinical treatments, the present study aimed to evaluate and compare methylation patterns using bisulfite sequencing PCR and evaluate the gene expression profile using real-time PCR in the genes CDKN2A, CDKN2B, CDC6, Bmi-1, CCND1, and RB1 in astrocytic tumors. Our results indicate that all the evaluated genes are not methylated independent of the tumor grade. However, the real-time PCR results indicate that these genes undergo progressive deregulation as a function of the tumor grade. In addition, the genes CDKN2A, CDKN2B, and RB1 were underexpressed, whereas CDC6, Bmi-1, and CCND1 were overexpressed; the increase in gene expression was significantly associated with decreased patient survival. Therefore, we propose that the evaluation of the expression levels of the genes involved in the RB/E2F pathway can be used in the monitoring of patients with astrocytomas in clinical practice and for the prognostic indication of disease progression.

BMPs as therapeutic targets and biomarkers in astrocytic glioma.

Astrocytic glioma is the most common brain tumor. The glioma initiating cell (GIC) fraction of the tumor is considered as highly chemoresistant, suggesting that GICs are responsible for glioma relapse. A potential treatment for glioma is to induce differentiation of GICs to a more benign and/or druggable cell type. Given BMPs are among the most potent inducers of GIC differentiation, they have been considered as noncytotoxic therapeutic compounds that may be of use to prevent growth and recurrence of glioma. We herein summarize advances made in the understanding of the role of BMP signaling in astrocytic glioma, with a particular emphasis on the effects exerted on GICs. We discuss the prognostic value of BMP signaling components and the implications of BMPs in the differentiation of GICs and in their sensitization to alkylating drugs and oncolytic therapy/chemotherapy. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer.

Promoter polymorphisms and methylation of E-cadherin (CDH1) and KIT in gastric cancer patients from northern Brazil.

UNLABELLED: The aim of this study was to verify genetic and epigenetic alterations in gastric cancer patients from Pará state, northern Brazil. MATERIALS AND METHODS: Exon 11 of KIT and two promoter polymorphisms (-160 C/A and -347 G/GA) of the E-cadherin gene (CDH1), and their correlation with the promoter methylation status were analyzed. RESULTS: No genetic alterations in KIT were found. Promoter polymorphisms revealed an increased probability of developing gastric cancer, especially of the diffuse-type, in patients carrying -160 A and -347 GA alleles. Analyses of CDH1 methylation suggested a significant difference between hypermethylated and non-hypermethylated samples, with a positive association between the -160 A allele and hypermethylation. CONCLUSION: Our results suggest that -160 A and -347 GA polymorphisms may increase the chance of developing gastric cancer in the studied population and that -160 A polymorphism seems to be related to the hypermethylation pattern of the promoter region of CDH1.

Comparative analysis of proliferative and genetic alterations in a primary chordoid meningioma and its recurrence using locus-specific probes and AgNOR.

Meningiomas are generally slow-growing benign tumours; however, recurrent cases are associated with a poor prognosis. As these tumours are commonly grouped according to their grade of malignancy, it is difficult to define tumour-specific alterations involved in their genesis and evolution. Genetic comparative studies of primary and recurrent tumours are important for the identification of the chromosomal, genetic and proliferative alterations that are possibly involved in the process of malignancy in this class of tumour. We performed interphase fluorescence in situ hybridization using region-specific probes comprising the genes MYCN, ERBB4, CDH1, ABR, ERBB2 and NF2 as well as AgNOR staining in a sample of primary and relapsed chordoid meningiomas. Significant differences were found in these samples regarding the genes NF2, MYCN, ABR and ERBB2. Cell proliferation levels also showed a significant difference. The results suggest the involvement of the MYCN gene in the evolution of meningiomas.

Epigenetic alterations in human brain tumors in a Brazilian population

Aberrant methylation of CpG islands located in promoter regions represents one of the major mechanisms for silencing cancer-related genes in tumor cells. We determined the frequency of aberrant CpG island methylation for several tumor-associated genes: DAPK, MGMT, p14ARF, p16INK4a, TP73, RB1 and TIMP-3 in 55 brain tumors, consisting of 26 neuroepithelial tumors, 6 peripheral nerve tumors, 13 meningeal tumors and 10 metastatic brain tumors. Aberrant methylation of at least one of the seven genes studied was detected in 83.6 percent of the cases. The frequencies of aberrant methylation were: 40 percent for p14ARF, 38.2 percent for MGMT, 30.9 percent for, p16INK4a, 14.6 percent for TP73 and for TIMP-3, 12.7 percent for DAPK and 1.8 percent for RB1. These data suggest that the hypermethylation observed in the genes p14ARF, MGMT and p16INK4a is a very important event in the formation or progression of brain tumors, since the inactivation of these genes directly interferes with the cell cycle or DNA repair. The altered methylation rate of the other genes has already been reported to be related to tumorigenesis, but the low methylation rate of RB1 found in tumors in our sample is different from that so far reported in the literature, suggesting that perhaps hypermethylation of the promoter is not the main event in the inactivation of this gene. Our results suggest that hypermethylation of the promoter region is a very common event in nervous system tumors.