EPCO-51. FUNCTIONAL ANALYSIS OF REGULATORY MUTATIONS IN PEDIATRIC BRAIN TUMORS

Abstract

Abstract Pediatric brain tumors are the primary cause of cancer related mortality in children and are characterized by low mutations burden. The known somatic drivers reside in the coding regions of the genome. The role of non-coding mutations in brain tumors is important yet underexplored. In this study we investigate the impact of regulatory region mutations in pediatric brain tumors. We studied 1.3 million open chromatin regions (OCRs) genome-wide from 9 studies including developing/adult brain, and cancer. Within these OCRs we identified recurring mutations in whole genome sequences from 1003 pediatric brain tumors from CBTN and PCAWG cohorts. A total of 567 OCRs with significantly recurring mutations were found, showing enrichment in brain-specific enhancers and in repressed polycomb regions in stem cells. The mutations in these OCRs resulted in motif disruption or creation of 217 transcription factor binding sites. Differential expression analysis of mutated vs nonmutated samples identified perturbations of gene or protein expression in 67 (RNA) and 16 (protein) OCR-gene pairs. Furthermore, 17 mutated OCRs were found to correlate with alterations in gene expression programs, indicating a potential regulatory role affecting multiple downstream genes. We further performed network analysis to explore clusters of OCR associated genes that share biological networks and pathways, and identified 24 clusters. Among these, OCR mutation-associated genes in 6 clusters showed a survival impact in patients. These 6 clusters mapped to pathways including mRNA decay and degradation, longevity regulating pathway, autophagy, p53 pathway, HIF2-alpha transcription factor network, pathways in cancer among others. In summary, we report functionally important regulatory elements in the genome that impact the biological processes in pediatric brain tumors.