Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression.

Autor:	Blomquist MR; Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.; Department of Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA., Ensign SF; Department of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, Arizona, USA., D'Angelo F; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA., Phillips JJ; Department of Pathology, University of California, San Francisco, San Francisco, California, USA., Ceccarelli M; BIOGEM, Ariano Irpino, Italy., Peng S; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, USA., Halperin RF; Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA., Caruso FP; Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy., Garofano L; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA.; Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy., Byron SA; Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA., Liang WS; Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA., Craig DW; Department of Translational Genomics, University of Southern California Keck School of Medicine, Los Angeles, California, USA., Carpten JD; Department of Translational Genomics, University of Southern California Keck School of Medicine, Los Angeles, California, USA., Prados MD; Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA., Trent JM; Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA., Berens ME; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, USA., Iavarone A; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA., Dhruv H; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, USA., Tran NL; Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.; Department of Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2020 Jun 19; Vol. 2 (1), pp. vdaa078. Date of Electronic Publication: 2020 Jun 19 (Print Publication: 2020).
DOI:	10.1093/noajnl/vdaa078
Abstrakt:	Background: Tumor heterogeneity underlies resistance and disease progression in glioblastoma (GBM), and tumors most commonly recur adjacent to the surgical resection margins in contrast non-enhancing (NE) regions. To date, no targeted therapies have meaningfully altered overall patient survival in the up-front setting. The aim of this study was to characterize intratumoral heterogeneity in recurrent GBM using bulk samples from primary resection and recurrent samples taken from contrast-enhancing (EN) and contrast NE regions. Methods: Whole exome and RNA sequencing were performed on matched bulk primary and multiple recurrent EN and NE tumor samples from 16 GBM patients who received standard of care treatment alone or in combination with investigational clinical trial regimens. Results: Private mutations emerge across multi-region sampling in recurrent tumors. Genomic clonal analysis revealed increased enrichment in gene alterations regulating the G2M checkpoint, Kras signaling, Wnt signaling, and DNA repair in recurrent disease. Subsequent functional studies identified augmented PI3K/AKT transcriptional and protein activity throughout progression, validated by phospho-protein levels. Moreover, a mesenchymal transcriptional signature was observed in recurrent EN regions, which differed from the proneural signature in recurrent NE regions. Conclusions: Subclonal populations observed within bulk resected primary GBMs transcriptionally evolve across tumor recurrence (EN and NE regions) and exhibit aberrant gene expression of common signaling pathways that persist despite standard or targeted therapy. Our findings provide evidence that there are both adaptive and clonally mediated dependencies of GBM on key pathways, such as the PI3K/AKT axis, for survival across recurrences. (© The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu