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

Mylan R Blomquist; Shannon Fortin Ensign; Fulvio D'Angelo; Joanna J Phillips; Michele Ceccarelli; Sen Peng; Rebecca F Halperin; Francesca P Caruso; Luciano Garofano; Sara A Byron; Winnie S Liang; David W Craig; John D Carpten; Michael D Prados; Jeffrey M Trent; Michael E Berens; Antonio Iavarone; Harshil Dhruv; Nhan L Tran

doi:10.1093/noajnl/vdaa078

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

Neurooncol Adv. 2020 Jun 19;2(1):vdaa078. doi: 10.1093/noajnl/vdaa078. eCollection 2020 Jan-Dec.

Authors

Mylan R Blomquist^{1

2}, Shannon Fortin Ensign³, Fulvio D'Angelo⁴, Joanna J Phillips⁵, Michele Ceccarelli⁶, Sen Peng⁷, Rebecca F Halperin⁸, Francesca P Caruso⁹, Luciano Garofano^{4

9}, Sara A Byron⁸, Winnie S Liang⁸, David W Craig¹⁰, John D Carpten¹⁰, Michael D Prados¹¹, Jeffrey M Trent⁸, Michael E Berens⁷, Antonio Iavarone⁴, Harshil Dhruv⁷, Nhan L Tran^{1

2}

Affiliations

¹ Department of Cancer Biology, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
² Department of Neurosurgery, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
³ Department of Hematology and Oncology, Mayo Clinic Arizona, Phoenix, Arizona, USA.
⁴ Institute for Cancer Genetics, Columbia University Medical Center, New York, New York, USA.
⁵ Department of Pathology, University of California, San Francisco, San Francisco, California, USA.
⁶ BIOGEM, Ariano Irpino, Italy.
⁷ Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, Arizona, USA.
⁸ Integrated Cancer Genomics Division, The Translational Genomics Research Institute, Phoenix, Arizona, USA.
⁹ Department of Science and Technology, Università degli Studi del Sannio, Benevento, Italy.
¹⁰ Department of Translational Genomics, University of Southern California Keck School of Medicine, Los Angeles, California, USA.
¹¹ Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Abstract

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.

Keywords: PI3K signaling; clonal evolution; contrast enhancement; glioblastoma; temporospatial heterogeneity.