Towards routine chromosome-scale haplotype-resolved reconstruction in cancer genomics

Cancer genomes are highly complex and heterogeneous. The standard short-read sequencing and analyticalmethods are unable to provide the complete and precise base-level structural variant (SV) landscape of cancergenomes. In this work, we applied high-resolution long accurate HiFi and long-range Hi-C sequencing to themelanoma COLO829 cancer line. Also, we developed an efficient graph-based approach that processes thesenew data types for chromosome-scale haplotype-resolved reconstruction to characterize the cancer precise SVlandscape. Our novel method produced high-quality phased scaffolds on the chromosome level on threehealthy samples and the COLO829 cancer line in less than half a day even in the absence of trio information,outperforming existing state-of-the-art methods. In the COLO829 cancer cell line, here we show that ourmethod identified and characterized precise somatic SV calls in important repeat elements that were missed inshort-read-based callsets. Our method also found the precise chromosome-level SV (germline and somatic)landscape with 19,956 insertions, 14,846 deletions, 421 duplications, 52 inversions and 498 translocations atthe base resolution. Our simple pstools approach should facilitate better personalized diagnosis and diseasemanagement, including predicting therapeutic responses.