Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures

Leland S. Hu (), Fulvio D’Angelo (), Taylor M. Weiskittel, Francesca P. Caruso, Shannon P. Fortin Ensign, Mylan R. Blomquist, Matthew J. Flick, Lujia Wang, Christopher P. Sereduk, Kevin Meng-Lin, Gustavo Leon, Ashley Nespodzany, Javier C. Urcuyo, Ashlyn C Gonzales, Lee Curtin, Erika M. Lewis, Kyle W. Singleton, Timothy Dondlinger, Aliya Anil, Natenael B. Semmineh, Teresa Noviello, Reyna A. Patel, Panwen Wang, Junwen Wang, Jennifer M. Eschbacher, Andrea Hawkins-Daarud, Pamela R. Jackson, Itamar S. Grunfeld, Christian Elrod, Gina L. Mazza, Sam C. McGee, Lisa Paulson, Kamala Clark-Swanson, Yvette Lassiter-Morris, Kris A. Smith, Peter Nakaji, Bernard R. Bendok, Richard S. Zimmerman, Chandan Krishna, Devi P. Patra, Naresh P. Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej M. Mrugala, Alyx B. Porter, Scott C. Beeman, Todd R. Jensen, Kathleen M. Schmainda, Yuxiang Zhou, Leslie C. Baxter, Christopher L. Plaisier, Jing Li, Hu Li, Anna Lasorella, C. Chad Quarles, Kristin R. Swanson, Michele Ceccarelli (), Antonio Iavarone () and Nhan L. Tran ()
Additional contact information
Leland S. Hu: Mayo Clinic Arizona
Fulvio D’Angelo: University of Miami
Taylor M. Weiskittel: Mayo Clinic Alix School of Medicine Minnesota
Francesca P. Caruso: University of Naples, “Federico II”
Shannon P. Fortin Ensign: Mayo Clinic Arizona
Mylan R. Blomquist: Mayo Clinic Arizona
Matthew J. Flick: Mayo Clinic Arizona
Lujia Wang: Georgia Institute of Technology
Christopher P. Sereduk: Mayo Clinic Arizona
Kevin Meng-Lin: Mayo Clinic
Gustavo Leon: Mayo Clinic Arizona
Ashley Nespodzany: Dignity Health
Javier C. Urcuyo: Mayo Clinic Arizona
Ashlyn C Gonzales: Dignity Health
Lee Curtin: Mayo Clinic Arizona
Erika M. Lewis: Arizona State University
Kyle W. Singleton: Mayo Clinic Arizona
Timothy Dondlinger: Imaging Biometrics, LLC, Elm Grove
Aliya Anil: Dignity Health
Natenael B. Semmineh: University of Texas MD Anderson Cancer Center
Teresa Noviello: University of Naples, “Federico II”
Reyna A. Patel: Mayo Clinic Arizona
Panwen Wang: Mayo Clinic Arizona
Junwen Wang: The University of Hong Kong
Jennifer M. Eschbacher: Dignity Health
Andrea Hawkins-Daarud: Mayo Clinic Arizona
Pamela R. Jackson: Mayo Clinic Arizona
Itamar S. Grunfeld: The City University of New York
Christian Elrod: Avinger Incorporated
Gina L. Mazza: Mayo Clinic Arizona
Sam C. McGee: Arizona State University
Lisa Paulson: Mayo Clinic Arizona
Kamala Clark-Swanson: Mayo Clinic Arizona
Yvette Lassiter-Morris: Mayo Clinic Arizona
Kris A. Smith: Barrow Neurological Institute, Dignity Health
Peter Nakaji: Banner University Medical Center, University of Arizona
Bernard R. Bendok: Mayo Clinic Arizona
Richard S. Zimmerman: Mayo Clinic Arizona
Chandan Krishna: Mayo Clinic Arizona
Devi P. Patra: Mayo Clinic Arizona
Naresh P. Patel: Mayo Clinic Arizona
Mark Lyons: Mayo Clinic Arizona
Matthew Neal: Mayo Clinic Arizona
Kliment Donev: Mayo Clinic Arizona
Maciej M. Mrugala: Mayo Clinic Arizona
Alyx B. Porter: Mayo Clinic Arizona
Scott C. Beeman: Arizona State University
Todd R. Jensen: Jensen Informatics LLC
Kathleen M. Schmainda: Medical College of Wisconsin
Yuxiang Zhou: Mayo Clinic Arizona
Leslie C. Baxter: Mayo Clinic Arizona
Christopher L. Plaisier: Arizona State University
Jing Li: Georgia Institute of Technology
Hu Li: Mayo Clinic
Anna Lasorella: University of Miami
C. Chad Quarles: University of Texas MD Anderson Cancer Center
Kristin R. Swanson: Mayo Clinic Arizona
Michele Ceccarelli: University of Miami
Antonio Iavarone: University of Miami
Nhan L. Tran: Mayo Clinic Arizona

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41559-1

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