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  • Analysis of Genomic Alterations in Tumor Subclones in a Patient with a Multifocal Glioblastoma

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    Elena I. Fomchenko MD, PhD; Zeynep Erson Omay PhD; Anita Huttner MD; Murat Gunel MD; Jennifer A. Moliterno Gunel MD

    Study Design:

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    Meeting: Congress of Neurological Surgeons 2018 Annual Meeting

    Introduction: Glioblastomas remain the most common primary malignant brain tumors with dismal prognosis and average survival of 15 months. Gliomas were thought of as clonal; however, multiple lines of evidence support a complex heterogeneous view of gliomas with the presence of multiple genetically different subclones. Radiation and chemotherapy introduce further variability and resistance by inducing genetic alterations allowing for selective expansion. Specifically of interest are multifocal glioblastomas, where multiple tumor foci could represent subclones arising independently, or derived from one another

    Methods: We describe a 55yo female with a newly diagnosed multifocal glioblastoma, who presented with a generalized seizure and was found to have contrast enhancing right frontal lesion and a non~enhancing right temporal abnormality on MRI. At the time of referral to our center, MRI showed progression with rim enhancement of both right frontal and temporal lesions. Patient underwent gross total resection of three tumors, with biopsies of frontal and temporal tumors sent for whole exome sequencing (WES)

    Results: Final pathology revealed IDH1 negative, MGMT unmethylated, ATRX positive, p53 negative, EGFR amplified, 1p19q deleted glioblastoma with 10% Ki67. WES yielded high ploidy EGFR amplifications and CDKN2A/PTEN deletions in all biopsies. Curiously, frameshift PTEN mutation identified in frontal glioblastoma specimen was not present in temporal biopsies. Conversely, EGFR missense mutation was identified in temporal specimen, but not frontal. These findings suggest that although frontal focus was prominent at presentation, it likely arose from less conspicuous temporal focus noted on the initial MRI

    Conclusions: WES of tumor foci in multifocal glioblastomas can help understand genetic basis of tumor heterogeneity, detect genetic alterations amenable to targeted therapies for individual subclones, and shed light onto glioma evolution. Understanding sequence of derivation of glioma subclones from original populations can identify proper radiologic readouts for tracking treatment efficacy and aid in monitoring resistant glioma subclones as they arise

    Patient Care: Understanding of glioma heterogeneity and clonality will ultimately lead to better targeted treatments

    Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of using whole exome sequencing to understand the genetic basis of glioma, 2) Appreciate heterogeneity of gliomas as it related to tumor evolution, 3) Identify potential applications to glioma treatment

    References: Erson Omay et al Longitudinal analysis of treatment~induced genomic alterations in gliomas. Genome Med. 2017 Feb 2; 9 (1):12 Harmanci et al Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun 2017 Feb 14; 8: 14433. Clark et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet 2016 Oct: 48 (10): 1253~9 Gunel et al. Molecular mechanisms underlying malignant progression of low grade IDH1 mutant meningiomas. Neurosurgery 2016 Aug; 63 Suppl 1:199 Erson Omay et al Somatic POLE mutations cause an ultra~mutated giant cell high grade glioma subtype with better prognosis. Neuro Oncol 2015 Oct 17 (10): 1356~64

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