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Exploring Pediatric Midline Glioma Biology: from Genomics to Liquid Biopsy Open Access

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Brain tumors are the leading cause of mortality among all cancer-related deaths in children. Among them, more than 90% of children diagnosed with midline gliomas (MLGs) often die within one year of diagnosis. Thus, there is an urgent need to elucidate the biology of these tumors with the chief objective to design molecularly informed clinical interventions and develop sensitive approaches for monitoring tumor response to therapy.Tumor cells extend from the primary site of tumor and disseminate throughout the brain of patients affected with MLGs. However, the molecular profile of primary and disseminated tumors as well as intra-tumor heterogeneity is not established. To address this gap in knowledge, we generated the molecular profile of primary and disseminated tumor samples, revealing that each MLG is driven by homogenously expressed driver mutations, including mutations in histone 3 encoding genes along with an obligate partner mutation. Our results reveal that MLGs consist of a previously unsuspected homogeneity of main driver mutations, which are present throughout the tumor spread. Thus, patients with MLG may benefit from being treated with precision therapy in order to molecularly target main driver mutations and consequently aberrant cancer signaling pathways. Our findings further indicate that needle biopsies recommended to orient care are representative of the main drivers in MLG.Stereotactic biopsy, being an invasive procedure, is seldom performed in pediatric patients affected with MLG. Notably, inability to accurately assess disease response is a major hurdle for developing successful therapeutic intervention. In contrast, liquid biopsy is emerging as a minimal-to-non-invasive method for detecting tumor-associated circulating DNA (ctDNA) in patient’s biofluid. We investigated the feasibility of a liquid biopsy approach for detecting main driver mutations in biofluids from MLG patients. We established a molecular-based tool to detect rare mutant alleles in MLGs in addition to magnetic resonance imaging with the main objective, to facilitate diagnosis and assess patients’ response to therapeutic intervention. Each patient’s response to precision therapies was successfully monitored in real-time by using ctDNA as a surrogate biomarker of tumor response. Hence, we provide the first evidence of the clinical translational utility to measure ctDNA for tumor surveillance and longitudinal monitoring of tumor response in childhood MLGs.Our collective findings contribute towards the design of personalized combination therapy targeting obligate partner mutations, and provide a novel approach to facilitate diagnosis and monitor disease response to therapy. These findings along with recent discoveries in the field set the stage for mitigating the devastation in pediatric patients wrought by MLGs.

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