22. Clinical utility of integrated genomic profiling in pediatric brain tumor

Abstract

Brain tumors are the most common solid tumor among children under 15, representing 20% of childhood cancers. Prognosis and therapeutic options vary dramatically based on histologic and molecular profiles. We have studied 222 brain tumors using the CHOP Comprehensive Solid Tumor Panel, which interrogates 238 cancer genes and 110 fusion partners. The most common tumors are pilocytic/pilomyxoid astrocytoma (67), medulloblastoma (23) and diffuse midline glioma (17). Clinically significant genomic alterations were identified in 93% of patients. Total 188 pathogenic SNVs/indels in 75 genes were reported 293 times in 135 cases. The most frequent mutations are BRAF V600E found in multiple tumors and H3F3A K28M exclusively in diffuse midline glioma. More than 1000 CNVs were reported in 136 cases. 19 fusions were detected 68 times in 64 cases. These results have significantly impacted patient care by providing diagnostic evidence in >90% of patients including 6 patients whose diagnosis was changed, prognostic evidence in 10% of patients, and therapeutic evidence in 17% of patients. Additionally, distinctive genomic signatures associated with specific tumor subtypes are identified/confirmed, enabling differentiation of diseases. 64% of pilocytic/pilomyxoid astrocytoma patients harbor fusions and over 50% are KIAA1549-BRAF. All diffuse midline glioma patients were H3F3A K28M positive and 53% show H3F3A gain. Isodicentric chr17q is highly enriched in non-WNT/non-SHH medulloblastoma. Loss/cnLOH of chr22 is found in 100% of ATRT cases, 50% of which display additional SMARCB1 mutations. Integrated genomic profiling in pediatric brain tumors allows a molecularly informative diagnosis per WHO guidelines, with additional prognostic and therapeutic benefits.