The Genetic Landscape of Human Glioblastoma and Matched Primary Cancer Stem Cells Reveals Intratumour Similarity and Intertumour Heterogeneity.

Chiara Pesenti,Marco Locatelli,Jole Costanza,Rosamaria Silipigni,Laura Fontana,Monica Miozzo,Paolo Rampini,Nicola Fusco,Stefania Elena Navone,Laura Guarnaccia,Silvia Tabano,Giovanni Marfia,Silvana Guarneri,Andrea Terrasi,Rolando Campanella

doi:10.1155/2019/2617030

Chiara Pesenti, Marco Locatelli + Show 13 more

Open Access

https://doi.org/10.1155/2019/2617030

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Abstract

Glioblastoma (GBM) is the most malignant human brain tumour, characterized by rapid progression, invasion, intense angiogenesis, high genomic instability, and resistance to therapies. Despite countless experimental researches for new therapeutic strategies and promising clinical trials, the prognosis remains extremely poor, with a mean survival of less than 14 months. GBM aggressive behaviour is due to a subpopulation of tumourigenic stem-like cells, GBM stem cells (GSCs), which hierarchically drive onset, proliferation, and tumour recurrence. The morbidity and mortality of this disease strongly encourage exploring genetic characteristics of GSCs. Here, using array-CGH platform, we investigated genetic and genomic aberration profiles of GBM parent tumour (n = 10) and their primarily derived GSCs. Statistical analysis was performed by using R software and complex heatmap and corrplot packages. Pearson correlation and K-means algorithm were exploited to compare genetic alterations and to group similar genetic profiles in matched pairs of GBM and derived GSCs. We identified, in both GBM and matched GSCs, recurrent copy number alterations, as chromosome 7 polysomy, chromosome 10 monosomy, and chromosome 9p21deletions, which are typical features of primary GBM, essential for gliomagenesis. These observations suggest a condition of strong genomic instability both in GBM as GSCs. Our findings showed the robust similarity between GBM mass and GSCs (Pearson corr.≥0.65) but also highlighted a marked variability among different patients. Indeed, the heatmap reporting Gain/Loss State for 21022 coding/noncoding genes demonstrated high interpatient divergence. Furthermore, K-means algorithm identified an impairment of pathways related to the development and progression of cancer, such as angiogenesis, as well as pathways related to the immune system regulation, such as T cell activation. Our data confirmed the preservation of the genomic landscape from tumour tissue to GSCs, supporting the relevance of this cellular model to test in vitro new target therapies for GBM.

Highlights

Glioblastoma (GBM) is the most common malignant primary tumour of the central nervous system (CNS)
Unlike normal stem cells, which acquire a quiescence after DNA damage, GBM stem cells (GSCs) express a plethora of proteins that promote cell survival [2]
Considering the importance of copy number alterations (CNAs) data, we focused on the comparison between genetic and genomic aberration profiles of GBM tumour masses and their primarily derived GSCs, investigating if GSC population harbours typical alterations different from the tumour bulk

Summary

Introduction

Glioblastoma (GBM) is the most common malignant primary tumour of the central nervous system (CNS). GBM is characterized by rapid progression and invasion, cell infiltration, Stem Cells International intense angiogenesis, resistance to radio- and chemotherapies, and high frequency of relapse. This aggressive behaviour is responsible for the poor prognosis, with a median survival of about 14 months and a 5-year survival rate of 5.1% [1]. GBM resistance to therapies and the high frequency of recurrence are mainly due to a subpopulation of tumourigenic stem-like cells, known as GBM stem cells (GSCs), able to hierarchically initiate, maintain, and spread the neoplasm. Unlike normal stem cells, which acquire a quiescence after DNA damage, GSCs express a plethora of proteins that promote cell survival [2]

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