Estudio de mutaciones en los genes IDH1 e IDH2 en una muestra de gliomas de población colombiana / Study of mutations in IDH1 and IDH2 genes in a sample of gliomas from Colombian population

Resumen Introducción. Los gliomas son los tumores primarios más comunes del sistema nervioso central y se clasifican de I a IV según su grado de malignidad. En recientes investigaciones se ha encontrado que su aparición está relacionada con mutaciones en el exón 4 de los genes que codifican las deshidrogenasas de isocitrato 1 y 2 (IDH1: codón 132; IDH2: codón 172). Objetivo. Determinar la frecuencia de mutaciones en los genes IDH1 e IDH2 en una muestra de gliomas de pacientes colombianos. Materiales y métodos. La extracción de ADN se hizo a partir de tejido tumoral. El exón 4 de los genes IDH1 e IDH2 se amplificó mediante PCR utilizando iniciadores específicos y, posteriormente, se secuenciaron. Para la determinación de las mutaciones, se emplearon los programas 4Peaksy MAFFT. Resultados. Se determinó la presencia de mutaciones en el gen IDH1 en el 34 % de las muestras, con predominio de la mutación no sinónima R132H. En el 7,5 % de los casos se detectaron mutaciones en el gen IDH2, principalmente las mutaciones no sinónimas R172K y R172W. Conclusiones. La frecuencia de mutaciones en los genes IDH1 e IDH2 en la muestra fue similar a la reportada en otros estudios. El análisis de estas mutaciones puede ser importante como factor pronóstico y para su uso como potenciales blancos terapéuticos en gliomas.

Abstract Introduction: Gliomas are the most common primary tumors of the central nervous system and, according to their malignancy, they are graded from I to IV. Recent studies have found that there is an association between gliomas and mutations in exon 4 of genes that codify for isocitrate dehydrogenases 1 and 2 (IDH1: codon 132; IDH2: codon 172). Objective: To establish the frequency of mutations in IDH1 and IDH2 in a sample of gliomas from Colombian population. Materials and methods: DNA was extracted from tumor tissue. The exon 4 of IDH1 and IDH2 was amplified by PCR using specific primers and subsequently sequenced. Mutations were determined using the 4Peaks MAFFT programs. Results: We found mutations in the IDH1 gene in 34% of the glioma samples, with a predominance of the nonsynonymous mutation R132H. Mutations in the IDH2 gene were found in 7.5% of cases, with a predominance of the nonsynonymous R172K and R172W mutations. Conclusions: The frequency of mutations in the IDH1 and IDH2 genes in the sample was similar to that reported in other studies. The analysis of these mutations may be important to establish prognostic factors and for the development of future therapeutic targets in gliomas.

Therapy for glioma: Indian perspective.

Central nervous system (CNS) are rare neoplasms with considerable heterogeneity and variation. The most common primary lesions of CNS are gliomas. A majority of the data about the demography and management of gliomas has emerged from the west. However, there may be considerable variation in the presentation, behavior, and response to treatment between patients in the western world and the Asian population. This article discusses gliomas with special reference to data from oncology centers in India.

Mutation analysis of gene PAX6 in human gliomas

Gliomas are the most common tumors of the central nervous system. In spite of the marked advances in the characterization of the molecular pathogenesis of gliomas, these tumors remain incurable and, in most of the cases, resistant to treatments, due to their molecular heterogeneity. Gene PAX6, which encodes a transcription factor that plays an important role in the development of the central nervous system, was recently recognized as a tumor suppressor in gliomas. The objective of the present study was to analyze the mutational status of the coding and regulating regions of PAX6 in 94 gliomas: 81 astrocytomas (11 grade I, 23 grade II, 8 grade III, and 39 grade IV glioblastomas), 5 oligodendrogliomas (3 grade II, and 2 grade III), and 8 ependymomas (5 grade II, and 3 grade III). Two regulating regions (SX250 and EIE) and the 11 coding regions (exons 4-13, plus exon 5a resulting from alternative splicing) of gene PAX6 were analyzed and no mutation was found. Therefore, we conclude that the tumor suppressor role of PAX6, reported in previous studies on gliomas, is not due to mutation in its coding and regulating regions, suggesting the involvement of epigenetic mechanisms in the silencing of PAX6 in these tumors.

Molecular basis of cholesterol feedback lesion in CNS tumours.

An important feature of malignant transformation of tumours is the loss of cholesterol feedback inhibition mechanism (cholesterol-feedback lesion) that regulates mevalonate pathway recognized to play a crucial role in cellular growth, death and differentiation. Recently, it was shown that Receptor-C(k)-dependent signalling regulates genes involved in maintaining cellular cholesterol homeostasis through a transcription factor sterol response element binding protein (SREBP) having affinity for sterol regulatory element (SRE) present in the promoter region of these genes. The present study revealed that CNS tumours exhibit overexpression of Receptor-C(k) gene product which was accompanied by their inability to express SREBP gene product and this phenomenon has the inherent capacity to initiate the cholesterol feedback lesion in these tumours. Based upon these and our earlier studies, we propose for the first time that this loss of cholesterol feedback control may be responsible for the initiation of these tumours.