Wakhan: reconstruction of chromosome-scale copy number profiles of tumor genomes with long-read sequencing

Abstract

A common signature of cancer genomes is a complex, rearranged karyotype, characterized by acquired gains or losses of chromosomal material, referred to as somatic copy number alterations (CNAs). Identification of haplotype-specific CNAs from bulk sequencing data is a key step in many short-read cancer genomic workflows; however, short reads have a limited phasing range. In contrast, long reads can directly phase genomic variants into contiguous haplotypes. Here, we present Wakhan, a long-read method for haplotype-specific CNA calling that can reconstruct longer, up to chromosome-scale CNA profiles of rearranged cancer genomes. Using multi-technology sequencing of a cell line panel, combined with high-quality de novo assemblies, we show that Wakhan CNA profiles have better consistency with sequencing data, as compared to the other popular short- and long-read CNA callers. Further, we show that in combination with accurate somatic SV calls, Wakhan CNA profiles provide additional insights into mutational processes in various breast cancer genomes. Finally, we apply Wakhan to multiple pediatric cancer samples and illustrate the high consistency with standard clinical genetic testing.