Integrated molecular and multiparametric MRI mapping of high-grade glioma identifies regional biologic signatures
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Published:2023-09-28
Issue:1
Volume:14
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Hu Leland S.ORCID, D’Angelo FulvioORCID, Weiskittel Taylor M., Caruso Francesca P.ORCID, Fortin Ensign Shannon P., Blomquist Mylan R., Flick Matthew J.ORCID, Wang Lujia, Sereduk Christopher P., Meng-Lin Kevin, De Leon Gustavo, Nespodzany Ashley, Urcuyo Javier C.ORCID, Gonzales Ashlyn C, Curtin LeeORCID, Lewis Erika M., Singleton Kyle W.ORCID, Dondlinger TimothyORCID, Anil Aliya, Semmineh Natenael B., Noviello TeresaORCID, Patel Reyna A., Wang Panwen, Wang JunwenORCID, Eschbacher Jennifer M., Hawkins-Daarud Andrea, Jackson Pamela R., Grunfeld Itamar S.ORCID, Elrod Christian, Mazza Gina L.ORCID, McGee Sam C., Paulson Lisa, Clark-Swanson Kamala, Lassiter-Morris Yvette, Smith Kris A., Nakaji Peter, Bendok Bernard R., Zimmerman Richard S., Krishna Chandan, Patra Devi P., Patel Naresh P., Lyons MarkORCID, Neal Matthew, Donev Kliment, Mrugala Maciej M., Porter Alyx B., Beeman Scott C., Jensen Todd R.ORCID, Schmainda Kathleen M., Zhou Yuxiang, Baxter Leslie C., Plaisier Christopher L.ORCID, Li Jing, Li HuORCID, Lasorella Anna, Quarles C. Chad, Swanson Kristin R., Ceccarelli Michele, Iavarone Antonio, Tran Nhan L.ORCID
Abstract
AbstractSampling 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.
Funder
U.S. Department of Health & Human Services | NIH | National Cancer Institute U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke Mayo Clinic U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences Ben and Catherine Ivy Foundation James S. McDonnell Foundation ADHS | Arizona Biomedical Research Commission Associazione Italiana per la Ricerca sul Cancro Ministry of Health, Italy | Agenzia Italiana del Farmaco, Ministero della Salute
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
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