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

Abstract

Most known cancer driver mutations are within protein coding regions of the genome, however, there are several important examples of oncogenic non-coding regulatory mutations. We developed a method to identify insertions and deletions (indels) in regulatory regions using aligned reads from chromatin immunoprecipitation followed by sequencing (ChIP-seq) or the assay for transposase-accessible chromatin (ATAC-seq). Our method, which we call BreakCA for Breaks in Chromatin Accessible regions, allows non-coding indels to be discovered in the absence of whole genome sequencing data, out-performs popular variant callers such as the GATK-HaplotypeCaller and VarScan2, and detects known oncogenic regulatory mutations in T-cell acute lymphoblastic leukemia cell lines. We apply BreakCA to identify indels in H3K27ac ChIP-seq peaks in 23 neuroblastoma cell lines and, after removing common germline variants, we identify 23 rare germline or somatic indels that occur in multiple neuroblastoma cell lines. Among them, 4 indels are candidate oncogenic drivers that are present in 4 or 5 cell lines, absent from the genome aggregation database of over 15,000 whole genome sequences, and within the promoters or first introns of known genes (PHF21A, ADAMTS19, GPR85 and RALGDS). In addition, we observe a rare 7bp germline deletion in two cell lines, which is associated with high expression of the histone demethylase KDM5B. Overexpression of KDM5B is prognostic for many cancers and further characterization of this indel as a potential oncogenic risk factor is therefore warranted.