Thursday, November 21, 2024
11/21/2024
ABSTRACT One of the greatest advances in pediatric brain tumor management has been the incorporation of tumor molecular findings in the diagnosis, prognostic stratification, and treatment of patients. Because of this, treatment options and outcomes for patients with specific alterations, including structural variants (SVs) resulting in fusions, have greatly improved. However, despite multiple research studies that show SVs are important for tumor development, maintenance, and progression, clinical analyses are generally limited to targeted gene sequencing panels (DNA +/- RNA) and targeted fluorescent in situ hybridization (FISH). This type of testing is sufficient for brain tumors that harbor classic genomic alterations, but inadequate for tumors that have atypical histological or molecular aberrations, oftentimes resulting in “negative” genomic testing. In addition, some of these tests have a long turnaround time, leading to delays in diagnosis and treatment. We are in great need for a clinical test that will allow for more accurate and rapid discovery of clinically significant SVs that can be used along with sequencing to create treatment plans with maximum benefit. Optical Genome Mapping (OGM) is a promising genomic technology that can help fill this molecular diagnostic gap. Our preliminary data utilizing about 60 pediatric brain tumor samples demonstrates the utility of OGM to identify previously known diagnostic SVs (i.e., BRAF-fusion), cryptic SVs that were not identified by clinical tests, and novel SVs that have never been described in pediatric brain tumors. Although novel in the field of pediatric brain tumors, OGM is being used clinically as a CLIA/CAP certified diagnostic test for Facioscapulohumeral Muscular Dystrophy (FSHD), a disorder that previously required southern blotting for diagnosis. More recently, the Augusta University Pathology Department submitted a successful Laboratory Developed Test application for OGM as a diagnostic test for hematologic malignancies to the American Medical Association. We propose to implement optical genome mapping (OGM) as a first line diagnostic approach for pediatric brain tumors in a clinical setting and utilize OGM to discover genomic SVs with potential clinical relevance. This study will be the first to generate pre-clinical evidence that brain tumor-driving genetic alterations can be rapidly identified using OGM, with the potential to guide clinical treatment plans for children with these tumors. By the end of the study period, OGM will be validated in CLIA/CAP certified laboratories (Children’s National Hospital Pathology, Bionano Laboratories, Augusta University), and a laboratory developed test application submitted pending promising results. This study will also utilize OGM for the discovery of novel pathogenic SVs in a large cohort of pediatric brain tumors samples, which may be used to improve diagnosis, allow for better outcome prediction, and ultimately advance therapies for affected children with brain tumors. The results of this study will have a direct impact on clinical care without requiring a clinical trial. Although this study will primarily focus on pediatric brain tumors, OGM can also be applied to other tumor types, expanding the therapeutic possibilities for children and adults diagnosed with these cancers.
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