Insight into spatial intratumoral genomic evolution in glioblastoma

Author:

Anand Atul1ORCID,Petersen Jeanette2,Andersen Lars2,Burton Mark2,Larsen Martin2,Erichsen Philip3,Pedersen Christian2,Poulsen Frantz2,Grupe Peter2,Thomassen Mads4,Kristensen Bjarne5

Affiliation:

1. Rigshospitalet, University of Copenhagen

2. Odense University Hospital

3. Rigshospitalet

4. University of Southern Denmark

5. Department of Clinical Medicine and Biotech Research and Innovation Center (BRIC), University of Copenhagen

Abstract

Abstract

Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through clinical positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome, exome and transcriptome analyses. Our findings unveil that hypermetabolic lesions, originating from hypometabolic lesions, exhibit strategic focal amplifications and deletions, and heightened APOBEC3 activity. Furthermore, we identify dipeptidase 1 as a novel vascular endothelial tip marker for hypermetabolic lesions in glioblastoma, facilitating angiogenesis and tumor metabolism by regulating transporter activities. This study underscores a spatial genomic evolution with diagnostic implications and elucidates challenges and opportunities crucial for the development of novel therapeutic strategies.

Publisher

Research Square Platform LLC

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