Glioblastoma Multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a large characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 46 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations were detected, we report that the large majority of them do not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain.

A Comprehensive Characterization of Mitochondrial DNA Mutations in Glioblastoma Multiforme

VIDONE, MICHELE;CALABRESE, CLAUDIA;GIROLIMETTI, GIULIA;KURELAC, IVANA;AMATO, LAURA BENEDETTA;IOMMARINI, LUISA;PORCELLI, ANNA MARIA;GASPARRE, GIUSEPPE
2015

Abstract

Glioblastoma Multiforme (GBM) is the most malignant brain cancer in adults, with a poor prognosis, whose molecular stratification still represents a challenge in pathology and clinics. On the other hand, mitochondrial DNA (mtDNA) mutations have been found in most tumors as modifiers of the bioenergetics state, albeit in GBM a characterization of the mtDNA status is lacking to date. Here, a large characterization of the burden of mtDNA mutations in GBM samples was performed. First, investigation of tumor-specific vs. non tumor-specific mutations was carried out with the MToolBox bioinformatics pipeline by analyzing 46 matched tumor/blood samples, from whole genome or whole exome sequencing datasets obtained from The Cancer Genome Atlas (TCGA) consortium. Additionally, the entire mtDNA sequence was obtained in a dataset of 104 fresh-frozen GBM samples. Mitochondrial mutations with potential pathogenic interest were prioritized based on heteroplasmic fraction, nucleotide variability, and in silico prediction of pathogenicity. A preliminary biochemical analysis of the activity of mitochondrial respiratory complexes was also performed on fresh-frozen GBM samples. Although a high number of mutations were detected, we report that the large majority of them do not pass the prioritization filters. Therefore, a relatively limited burden of pathogenic mutations is indeed carried by GBM, which did not appear to determine a general impairment of the respiratory chain.
Michele Vidone;Rosanna Clima;Mariangela Santorsola;Claudia Calabrese;Giulia Girolimetti;Ivana Kurelac;Laura Benedetta Amato;Luisa Iommarini;Elisa Trevisan;Marco Leone;Riccardo Soffietti;Isabella Morra;Giuliano Faccani;Marcella Attimonelli;Anna Maria Porcelli;Giuseppe Gasparre
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/423566
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