Patrones de amplificación de EGFR en el glioblastoma, e identificación de biomarcadores implicados en sus principales vías de señalización

In Spain, more than 4,000 people will be diagnosed annually with a malignant brain tumor, being the majority of them malignant gliomas. Most are glioblastomas (grade IV) (GB), these being the most aggressive type. The average survival for patients treated with the standard protocol is expected to be around 15 months. Such reduced life expectancy is due to the fact that they are highly proliferative and heterogeneous tumors. This underlines the need to look for alternatives to improve their management. The studies of this thesis focus on characterizing biomarkers and genetic alterations in the different presentation status of EGFR that can better address the knowledge of this tumor as well as confirm its prognostic or predictive value of response to treatment. Articles I and II explored different biomarkers finding that the Major Vault Protein (MVP) and the methylation status of ADP 1 Ribosylation Factor (ARF1) are markers that provide information on the molecular mechanisms underlying the aggressive behavior of GB. In article I, the role of the MVP protein within the different EGFR status and its relationship with PTEN is studied, as well as its interrelationship with resistance to multiple drugs by reducing the cellular accumulation of chemotherapeutic agents in these patients. This study showed that an increase in MVP expression is an independent prognostic factor for worse clinical response to chemotherapy and/or overall survival. The purpose of the second article was to characterize the methylation status of genes relevant to GB that would be associated with alterations in the EGFR gene and that could be biomarkers of better prognosis. A significant association with a molecule involved in the vesicular trafficking process, ARF1, was found. The results presented in this publication provided a basis for a new hypothesis connecting EGFR gene amplification with ARF1 gene promoter methylation, vesicle trafficking, membrane turnover and increased tumor metabolism. The mechanisms underlying these connections and their functional consequences remain to be established. In the third article, somatic copy number alterations (SCNA), along with EGFRvIII detection and EGFR amplification, were analyzed in a series of 137 GB patients. Statistically significant associations between the amplification of EGFR and/or EGFRvIII, and SCNA in CDKN2A, MSH6, MTAP and ADD3 were found, being both EGFRvIII and ADD3 losses independent markers of poor prognosis. Most of these genes were involved in the main EGFR signaling pathways. In conclusion, the results of these studies provide new insights into genetic alterations that are probably involved in the mechanisms that lead to the development of glioblastoma.