Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">Background.</div>Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients.<div class="boxTitle">Methods.</div>We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes.<div class="boxTitle">Results.</div>Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with <span style="font-style:italic;">BCOR</span> alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame <span style="font-style:italic;">RAF1</span> fusion in a <span style="font-style:italic;">BRAF</span> wild-type pleomorphic xanthoastrocytoma, an inactivating <span style="font-style:italic;">ASXL1</span> mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of <span style="font-style:italic;">MAP2K1</span> in a low-grade astrocytic neoplasm.<div class="boxTitle">Conclusions.</div>Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.</span>

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