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 as well as 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, as well as 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 as well as 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. This article is protected by copyright. All rights reserved.

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