Faculty, Staff and Student Publications

Language

English

Publication Date

9-28-2023

Journal

Nature Communications

DOI

10.1038/s41467-023-41559-1

PMID

37770427

PMCID

PMC10539500

PubMedCentral® Posted Date

9-28-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate abundant private mutations or enrichment in immune cell signatures. These NE phenotypes are non-invasively identified through normalized K2 imaging signatures, which discern cell size heterogeneity on dynamic susceptibility contrast (DSC)-MRI. NE tumor populations predicted to display increased cellular proliferation by mean diffusivity (MD) MRI metrics are uniquely associated with EGFR amplification and CDKN2A homozygous deletion. The biophysical mapping of infiltrative HGG potentially enables the clinical recognition of tumor subpopulations with aggressive molecular signatures driving tumor progression, thereby informing precision medicine targeting.

Keywords

Humans, Brain Neoplasms, Multiparametric Magnetic Resonance Imaging, Homozygote, Sequence Deletion, Glioma, Magnetic Resonance Imaging, Biological Products, Cancer genomics, Cancer imaging

Published Open-Access

yes

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