Detailed longitudinal sampling of glioma stem cells in situ reveals Chr7 gain and Chr10 loss as repeated events in primary tumor formation and recurrence

Abstract

Intratumoral heterogeneity at the genetic, epigenetic, transcriptomic, and morphologic levels is a commonly observed phenomenon in many aggressive cancer types. Clonal evolution during tumor formation and in response to therapeutic intervention can be predicted utilizing reverse engineering approaches on detailed genomic snapshots of heterogeneous patient tumor samples. In this study, we developed an extensive dataset for a GBM case via the generation of polyclonal and monoclonal glioma stem cell lines from initial diagnosis, and from multiple sections of distant tumor locations of the deceased patient's brain following tumor recurrence. Our analyses revealed the tissue-wide expansion of a new clone in the recurrent tumor and chromosome 7 gain and chromosome 10 loss as repeated genomic events in primary and recurrent disease. Moreover, chromosome 7 gain and chromosome 10 loss produced similar alterations in mRNA expression profiles in primary and recurrent tumors despite possessing other highly heterogeneous and divergent genomic alterations between the tumors. We identified ETV1 and CDK6 as putative candidate genes, and NFKB (complex), IL1B, IL6, Akt and VEGF as potential signaling regulators, as potentially central downstream effectors of chr7 gain and chr10 loss. Finally, the differences caused by the transcriptomic shift following gain of chromosome 7 and loss of chromosome 10 were consistent with those generally seen in GBM samples compared to normal brain in large-scale patient-tumor data sets.

RNA processing genes characterize RNA splicing and further stratify lower-grade glioma

“…The median overall survival (OS) of patients with glioblastoma (GBM; WHO grade IV) is only approximately 15 months (1,3,4). Patients with lower-grade diffuse glioma (LGG, WHO grade II/III) have a relatively favorable prognosis, but these tumors evolve and most relapse as therapy-resistant higher-grade gliomas over time (5)(6)(7).…”

Genomic and Transcriptomic Characterization of the New Human Glioblastoma Cell Line AHOL1

“…We also identified that the up-regulation of ETV1, an important oncogene involved in transcriptional regulatory processes in GBMs [112], was due to a chromosome 7 gain in AHOL1 genome. It has been shown that chromosome 7 gain is a key event in G-CIMP-negative GBMs [23,113], and high expression of ETV1 may be a potential downstream effector of chromosome 7 gain [112]. Previous study also revealed that ETV1 is fused with DGKB and may act as oncogenic drivers in pediatric high-grade gliomas [114].…”

Molecular Markers of Therapy-Resistant Glioblastoma and Potential Strategy to Combat Resistance

“…Suppressing the apoptotic potential through gene expression regulation in the irradiated cells was a proposed mechanism that explained the radioresistant nature of the irradiated GBM cells [ 107 , 108 ]. Many apoptotic genes discovered in our study were known to play major roles in attenuating GBM apoptosis, especially, BBC3 , DCC , BEX2 , CASP1 , IL1B , and SFRP2 [ 115 , 116 , 117 , 118 , 119 , 120 ]. GBM cells produce an immunosuppressive microenvironment to escape immune surveillance and enhance their own survival, and this can be accomplished through the secretion of transforming growth factor β ( TGF-β ) to block T cell activation and proliferation [ 121 ].…”