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

Mehmet Baysan, Kevin Woolard, Margaret C. Cam, Wei Zhang, Hua Song, Svetlana Kotliarova, Demosthenes Balamatsias, Amanda Linkous, Susie Ahn, Jennifer Walling, Galina I. Belova, Howard A. Fine*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2002-2013
Number of pages12
JournalInternational Journal of Cancer
Volume141
Issue number10
DOIs
Publication statusPublished - 15 Nov 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 UICC

Funding

1Department of Computer Science & Engineering, Istanbul Sehir University, Istanbul, 34662, Turkey 2Department of Pathology, Microbiology, and Immunology, University of California, Davis, CA 3Office of Science and Technology Resources, National Cancer Institute, National Institutes of Health, Bethesda, MD 4Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 5Center for Scientific Review, National Institutes of Health, Bethesda, MD 6Sandra and Edward Meyer Cancer Center, Weill Cornell Medical College, New York, NY 7Cancer Genetics Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 8Office of The Clinical Director, National Cancer Institute, National Institutes of Health, Bethesda, MD

FundersFunder number
Immunology, University of California, Davis, CA 3Office of Science and Technology Resources
Istanbul Sehir University
National Institutes of Health
National Cancer Institute
Weill Cornell Medical College

    Keywords

    • clonal development
    • glioblastoma
    • glioma stem cells
    • intratumor heterogeneity

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