TB-20PRELIMINARY EXPERIENCE WITH WHOLE EXOME SEQUENCING FOR CHILDREN WITH CNS TUMORS

Abstract

Introduction: The Precision in Pediatric Sequencing (PiPSeq) program at Columbia University was initiated in 2014, offering genomic sequencing for children with high-risk or recurrent cancers, including primary CNStumors,thesubjectofthisreport.Methods:Afterobtaininginformed consent and confirming tissue availabilityand adequacy, CNS tumor samples and peripheral blood were subjected to whole exome sequencing (WES) and transcriptome analysis in a certified clinical laboratory. Results: Of the first 19 CNS tumor cases (11 male, 8 female, median age at diagnosis 11 years), adequate specimens were available from 16 (84%). No patient had a mutation with proven relevance for tumor-specific targeted therapy (tier 1), but 7 (44%) had mutations of potential clinical utility in established cancer genes or pathways (tier 2), including H3F3A, ATM, FGFR1, KIT/KDR, DICER1, and TP53. Mutations in consensus cancer genes (tier 3) were found in one case (novel M997 frameshift mutation in KDM6A), and somatic variants of uncertain significance were identified in 4 cases. TranscriptomeanalysisrevealedanovelTMEM106B-BRAFfusion(pleomorphic xanthoastrocytoma), a novel germline VHL variant (ependymoma, with overexpression of “group A” genes), and an EWSR1-WT1 fusion (primary CNS DSRCT). Conclusion: Tumor and germline WES with transcriptomeinchildrenwithprimaryCNStumorsisfeasible,andinhalfofevaluable cases revealed mutations in a variety of cancer-associated genes, some potentially actionable.