Vol. 3 No. 1 - Mar 2017

Tomography is a scientific journal for publication of articles in imaging research

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MRI-Guided Stereotactic Biopsy of Murine GBM for Spatiotemporal Molecular Genomic Assessment Stefanie Galbán 1,2 , Wajd N. Al-Holou 4 , Hanxiao Wang 1,2 , Amanda R. Welton 1,2 , Kevin Heist 1,2 , Xin Kathy Hu 4 , Roeland GW Verhaak 4 , Yuan Zhu 5 , Carlos Espinoza 1,2 , Thomas L. Chenevert 1,2 , Ben A. Hoff 1,2 , Craig J. Galbán 1,2 , and Brian D. Ross 1,2 1 Center for Molecular Imaging, University of Michigan Medical School, Ann Arbor, Michigan; 2 Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan; 3 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan; 4 The University of Texas MD Anderson Cancer Center, Houston, Texas; and 5 Children's National Medical Center, Washington, DC Corresponding Author: Brian D. Ross, PhD Department of Radiology, Center for Molecular Imaging, University of Michigan School of Medicine, Biomedical Sciences Research Building, 109 Zina Pitcher Place, Ann Arbor MI 48109-2200; E-mail: Key Words: MRI-guided biopsy, murine studies, genomic analysis, glioma Abbreviations: Glioblastoma (GBM), magnetic resonance imaging (MRI), gadolinium (Gd), magnetic resonance (MR), false discovery rate (FDR), ingenuity pathway analysis (IPA), 3-dimensional (3D), RNA sequencing (RNA-Seq) Brain tumor biopsies that are routinely performed in clinical settings significantly aid in diagnosis and stag- ing. The aim of this study is to develop and evaluate a methodological image-guided approach that would allow for routine sampling of glioma tissue from orthotopic mouse brain tumor models. A magnetic reso- nance imaging-guided biopsy method is presented to allow for spatially precise stereotaxic sampling of a murine glioma coupled with genome-scale technology to provide unbiased characterization of intra- and in- tertumoral clonal heterogeneity. Longitudinal and multiregional sampling of intracranial tumors allows for successful collection of tumor biopsy samples, thus allowing for a pathway-enrichment analysis and a tran- scriptional profiling of RNA sequencing data. Spatiotemporal gene expression pattern variations revealing genomic heterogeneity were found. INTRODUCTION Glioblastoma (GBM) is the most common and aggressive intra- cranial tumor in adults. Despite decades of research, survival remains dismal, with a mean survival time of 15 months and a mean 5-year survival rate of ,10% (1-3). The standard therapy consists of maximal safe surgical resection, followed by radia- tion and then chemotherapy with temozolomide, and this pro- tocol has changed very little since its inception (2). Although many patients initially respond, GBM inevitably recurs in most patients (1). Given its poor prognosis, GBM is a perfect candidate for targeted therapy using precision medicine; thus, understanding the genetic profile of GBM is vital. However, known spatial and temporal tumor heterogeneity is recognized as a significant obstacle for accurate diagnosis impeding the use of targeted therapies. GBM is among the first tumor types for which in-depth genomic analyses were performed (4), and integrated genomic analyses performed in a large cohort of patients uncovered complex clonal heterogeneity (4), intertumoral heterogeneity (5-10), and intratumoral heterogeneity (11-14). Recent stud- ies have revealed that customized treatments targeting spe- cific mutations may not be efficacious in altering patient outcomes (15). Although in this case the cause of treatment failure is unclear, previous studies have shown that between 67% and 91% of posttreatment failures no longer harbored the target mutation (16, 17). This is probably because of clonal expansion of cells outside the targeted mutation. GBM is also known to change its molecular signature with treat- ment (18). These findings reflect the highly dynamic genetic evolution present in GBM, confounding the elucidation of its complete genetic landscape. Multiregional tumor sampling is ideal in GBM and other tumor types, but it is often impractical and potentially risky for routine clinical application (19, 20). Furthermore, tumor sam- pling during different treatment phases is often clinically unin- dicated. However, precise mechanisms underlying tumor heter- ogeneity and its functional significance can be evaluated in preclinical models for discovery of driver mutations, discovery of mechanisms of drug resistance, identification of genetic and imaging biomarkers, and development of clone-specific cancer therapies. Here, we devised and successfully showed a magnetic res- onance imaging (MRI)-guided stereotactic biopsy method for isolation and functional profiling of tumoral heterogeneity to ADVANCES IN BRIEF ABSTRACT © 2017 The Authors. Published by Grapho Publications, LLC This is an open access article under the CC BY-NC-ND license ( ISSN 2379-1381 TOMOGRAPHY.ORG | VOLUME 3 NUMBER 1 | MARCH 2017 9

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