Phased Mutations and Complex Rearrangements in Human Prostate Cancer Cell Lines through Linked-Read Whole Genome Sequencing

A limited number of cell lines have fueled the majority of preclinical Prostate cancer research, yet comprehensive whole genome sequencing with allelic phasing of somatic genome alterations has not been undertaken to date. Here, we utilized whole genome Linked-read sequencing to obtain haplotype information from the seven most commonly used PCa cell lines PC3, LNCaP, DU145, CWR22Rv1, VCaP, LAPC4, MDA-PCa-2b, four castrate resistant subclones LNCaP_Abl, LNCaP_C42b, VCaP-CR, LAPC4-CR, and an immortalized prostate epithelial line RWPE-1. Phasing of mutations allowed derivation of Gene-level Haplotype to assess whether a gene harbored heterozygous mutations in one or both alleles, providing a comprehensive catalogue of mono or bi-allelically inactivated genes. Phased structural variant analysis allowed identification of complex rearrangement chains consistent with chromothripsis and chromoplexy, with breakpoints occurred across a single allele, providing further evidence that complex SVs occurred in a concerted event, rather than through accumulation of multiple independent rearrangements. Additionally, comparison of parental and CR subclones revealed previously known and novel genomic alterations associated with the CR clones.