Genomic approaches to guide molecular classification of glioma

Duke University, Durham NC

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Abstract

? DESCRIPTION (provided by applicant): Malignant gliomas account for more than 80% of all primary brain malignancies and 14,000 deaths in the U.S. annually. Despite aggressive treatment, malignant gliomas are largely fatal, as their invasive nature renders them prone to rapid recurrence. Gliomas are classified according to histopathologic criteria which are critical t treatment planning, as certain subtypes show increased sensitivity to particular therapeutic agents. However, gliomas often exhibit extensive tumor heterogeneity and ambiguity among histologic features, leading to subjectivity in diagnosis and low concordance rates among neuropathologists. Recently, a number of large-scale genomic studies identified mutations in the TERT promoter and IDH1/2 in ~80% of all gliomas. Based on the occurrence of these mutations, gliomas can be classified into objective molecular subtypes that stratify patients into clear prognostic subgroups more effectively than by histology alone. However, current sequencing-based methods to identify these alterations are limited by low sensitivity (40% tumor cellularity), a major constraint on their clinical utility in the context of diffusely infiltrativegliomas. Importantly, this work also revealed that 20% of gliomas lack these alterations, delineating a subset of tumors known as the TERT/IDH wildtype gliomas. Objectives/Hypothesis: Preliminary studies indicate that TERT promoter and IDH mutations can effectively stratify patients into genetic subtypes, however current mutation detection methods lack sensitivity (Sanger sequencing) or are overly time-consuming (next-generation sequencing). We hypothesize that a single-step qPCR-based approach can provide more sensitive and rapid detection of these mutations and practical utility in glioma diagnosis by detecting low-abundance mutations (e.g., poorly sampled tumors). Additionally, we hypothesize that the yet undefined TERT/IDH wildtype gliomas will harbor a unique set of genetic alterations and exhibit distinct mechanisms of telomere maintenance from other gliomas. By using genetic techniques such as allele-specific qPCR and next generation sequencing, the following specific aims will be completed: Aim 1: Develop a sensitive diagnostic tool for detection of the TERT promoter and IDH1/2 hotspot mutations for molecular classification of glioma Aim 2: Characterize the major genetic and transcriptional alterations in the TERT/IDH wildtype gliomas and investigate their mechanisms of telomere maintenance. The long-term goal of this study is to identify genetic alterations that can act as biomarkers for more accurate diagnosis and treatment of glioma based on patient-specific molecular signatures. By developing a sensitive diagnostic for these critical TERT and IDH alterations, we will facilitate accurate diagnosis and prognostication of glioma patients. Comprehensively profiling the landscape of the TERT/IDH wildtype tumors will help identify novel biomarkers and therapeutic targets for this uncharacterized subset of glioma patients.