BreakCA, a method to discover indels using ChIP-seq and ATAC-seq reads, finds recurrent indels in regulatory regions of neuroblastoma genomes

Abstract

10Most known cancer driver mutations are within protein coding regions of the genome, however, there are 11 several important examples of oncogenic non-coding regulatory mutations. We developed a method to 12 identify insertions and deletions (indels) in regulatory regions using aligned reads from chromatin 13 immunoprecipitation followed by sequencing (ChIP-seq) or the assay for transposase-accessible 14 chromatin (ATAC-seq). Our method, which we call BreakCA for Breaks in Chromatin Accessible 15 regions, allows non-coding indels to be discovered in the absence of whole genome sequencing data, out-16 performs popular variant callers such as the GATK-HaplotypeCaller and VarScan2, and detects known 17 oncogenic regulatory mutations in T-cell acute lymphoblastic leukemia cell lines. We apply BreakCA to 18 identify indels in H3K27ac ChIP-seq peaks in 23 neuroblastoma cell lines and, after removing common 19 germline variants, we identify 23 rare germline or somatic indels that occur in multiple neuroblastoma 20 cell lines. Among them, 4 indels are candidate oncogenic drivers that are present in 4 or 5 cell lines, 21 absent from the genome aggregation database of over 15,000 whole genome sequences, and within the 22 promoters or first introns of known genes (PHF21A, ADAMTS19, GPR85 and RALGDS). In addition, we 23