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Int J Cancer. 2017 Nov 15;141(10):2002-2013. doi: 10.1002/ijc.30887. Epub 2017 Aug 21.

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

Author information

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

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.

KEYWORDS:

clonal development; glioblastoma; glioma stem cells; intratumor heterogeneity

PMID:
28710771
DOI:
10.1002/ijc.30887
[Indexed for MEDLINE]
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