Gene study predictors radiosensitivity and survival in patients treated with radiation therapy and glioblastoma temozolomide

Abstract

Glioblastoma multiforme (GBM) is the primary tumor of the central nervous system most frequently in adults, with an average survival of approximately 12 months. Multiple genetic and epigenetic alterations present in this tumor determine their biology and phenotype, quite aggressive. The standard treatment of GBM is a multidisciplinary approach involving neurosurgery, radiotherapy (RT) and chemotherapy (CT). The best response rates and survival of patients diagnosed with GBM have been associated with the combined treatment of surgery (with maximum possible resection), followed by RT associated with Temozolamide (TMZ) in radiosensitising character followed by adjuvant TMZ. Several studies have evaluated gene expression signatures that could predict the clinical and biological behavior of neoplasms. In experiments involving cell lines cultures using large-scale genetic analysis, 10 genes were identified (RA, cJun, STAT1, PKC RelA, c-Abl, SUMO1, CDK1, HDAC1 and IRF1) associated with radiosensitivity, creating a coefficient called Radiosensitivity Index (RSI). This coefficient was validated for rectal tumors, esophagus, head and neck tumors and breast treated with radiotherapy associated or not chemotherapy, however, similar studies have not been conducted considering samples of primary glioblastoma multiforme. Objectives: The aim of this work is to study the expression of genes involved in the RSI and the MGMT gene in human primary tumor samples from GBM, seeking to identify their association with radiosensitivity and survival. Patients and methods: The analyzes of the relative expression of the AR gene, cJun, STAT1, PKC, RelA, c-Abl, SUMO1, CDK1, HDAC1, IRF1 and MGMT will be performed using the PCR technique in real time. Information contained in the medical record of the patient related to the clinical, epidemiological, sociodemographic and clinical and radiological evolution will be collected (toxicities, tumor pseudoprogressão and tumor response) and clinical outcome (overall survival, progression-free survival and survival rates 6 and 12 months after diagnosis). Considering a significance level of 5% and the power of 80%, will be analyzed 90 patients, to be divided after survival analysis in radiosensitive and radioresistant. Will be compared in these two groups to differential expression of RSI / MGMT. The association of categorical qualitative variables and gene expression will be performed using the Mann-Whitney test. Survival analysis will be performed by non-parametric Kaplan-Meier method. The effect of the interaction between the marking of the RSI / MGMT with the variables of interest will be assessed by logistic regression model. (AU)