Abstract 3039: Role of IDH mutation status on molecular and spatial heterogeneity in glial tumors across progression and recurrence
Authors: Berens Michael E. , Barnholtz-Sloan Jill S. , Rusu Miribella , Graf John , Sood Anup , Cho Sanghee , Zavodszky Maria , Byron Sara , Halperin Rebecca , Fritz Yi , Kim Seungchan , Ginty Fiona 
Published: August 2018

Abstract
We developed and deployed a workflow for generating multi-scale, multiparametric imaging data, feature extraction and/or converting to higher scales which equips multiple analysis approaches to differentiate clinically variable phenotypes of glial tumors. The workflow quantifies spatial heterogeneity (concordance of adjoining cells) and molecular heterogeneity (varied cell states determined by protein abundance) of glial tumors at the genomic, tissue, and medical imaging scales including IDH mutation status and progression/recurrence status. A panel of 24 multiplexed immunofluorescence (MxIF) markers (addressing 9 hallmarks of cancer) was used to profile single cells (in the thousands) in tissue sections from each of 31 glial tumors (ranging from primary grade II to IV, and recurrent grade IV). Pre-resection multi-parameter MR images were feature extracted from discreet habitats (necrosis, enhancing, and edema); whole exome and transcriptome sequencing from bulk viable tumor were analyzed. By MxIF, the various states of individual cells from treatment-naive patient specimens resolved unsupervised into 7 clusters, for which Cluster 2 (including cells from 9 patients) and Cluster 6 (including cells from 8 patients) contained the two larger bundles of patient cases. When separated into IDHmt and IDHwt cases, cells from IDHmt cases frequently contained cell populations dominated by a single cluster (low molecular heterogeneity); cells from cases with IDHwt represented multiple different clusters (high molecular heterogeneity). In grade III astrocytomas, and grade IV recurrent glioblastomas, spatial heterogeneity of the hallmark “inducing angiogenesis” was elevated in the IDHmt tumors compared to IDHwt, while between the same groups, molecular heterogeneity was lower in the IDHmt cases than wild type. Edema from T1w post contrast MR imaging was found to be elevated in IDHwt gliomas relative to IDHmt, while enhancement was reduced in IDHwt compared to IDHmt tumors. The findings demonstrate that IDHmt gliomas, irrespective of grade, show less edema, greater enhancement, and greater spatial heterogeneity of the “inducing angiogenesis” hallmark but lower molecular heterogeneity than IDHwt tumors. Molecular heterogeneity of “cancer invasion” also differed between IDHmt and IDHwt cases. Longer survival duration following diagnosis for patients with IDHmt gliomas may reflect generalized altered molecular and spatial heterogeneity, which is a phenotype evident on medical imaging. [Clinically-annotated specimens originated from the Ohio Brain Tumor Study and the Ivy GBM Clinical Trials Consortium]
Citation Format: Michael E. Berens, Jill S. Barnholtz-Sloan, Miribella Rusu, John Graf, Anup Sood, Sanghee Cho, Maria Zavodszky, Sara Byron, Rebecca Halperin, Yi Fritz, Seungchan Kim, Fiona Ginty. Role of IDH mutation status on molecular and spatial heterogeneity in glial tumors across progression and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3039.