TY - JOUR
T1 - Temporospatial genomic profiling in glioblastoma identifies commonly altered core pathways underlying tumor progression
AU - Blomquist, Mylan R.
AU - Ensign, Shannon Fortin
AU - D'Angelo, Fulvio
AU - Phillips, Joanna J.
AU - Ceccarelli, Michele
AU - Peng, Sen
AU - Halperin, Rebecca F.
AU - Caruso, Francesca P.
AU - Garofano, Luciano
AU - Byron, Sara A.
AU - Liang, Winnie S.
AU - Craig, David W.
AU - Carpten, John D.
AU - Prados, Michael D.
AU - Trent, Jeffrey M.
AU - Berens, Michael E.
AU - Iavarone, Antonio
AU - Dhruv, Harshil
AU - Tran, Nhan L.
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - clonal evolution
KW - contrast enhancement
KW - glioblastoma
KW - PI3K signaling
KW - temporospatial heterogeneity
UR - http://www.scopus.com/inward/record.url?scp=85102924720&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102924720&partnerID=8YFLogxK
U2 - 10.1093/noajnl/vdaa078
DO - 10.1093/noajnl/vdaa078
M3 - Article
AN - SCOPUS:85102924720
VL - 2
JO - Neuro-Oncology Advances
JF - Neuro-Oncology Advances
SN - 2632-2498
IS - 1
M1 - vdaa078
ER -