Abstract
Castration-resistant prostate cancer (CRPC) is an aggressive disease exhibiting multiple epigenomic subtypes: androgen receptor-dependent CRPC-AR, and lineage plastic subtypes CRPC-SCL (stem cell-like), CRPC-WNT (Wnt-dependent), and CRPC-NE (neuroendocrine). By transcriptomic profiling of tissue, and whole-genome sequencing (WGS) of tissue and cell-free DNA (cfDNA) from 500 samples, we relate genomic variants with epigenomic state. We find lineage plasticity is associated with higher epigenomic and genomic heterogeneity. Samples with CRPC-SCL show higher chromosomal instability. We find DNA alterations, particularly chromosomal rearrangements, in the YAP/TAZ pathway associated with CRPC-SCL. For example, complex rearrangements on chromosome 4, which are supported by patient-matched 3D genome architecture data, decrease promoter interactions of MOB1B , a YAP/TAZ pathway inhibitor, with its enhancers. Together, the genomic variants in the pathway can predict CRPC-SCL with 79% accuracy. We show the utility of cfDNA WGS for joint inference of epigenomic state and genomic variants, which can guide patient stratification for clinical decisions. SIGNIFICANCE: This study reveals genomic variants associated with the presence of lineage-plastic CRPC stem cell-like state. We leverage the utility of minimally invasive cfDNA sequencing to obtain genomic and epigenomic insights about CRPC heterogeneity, which have implications for patient stratification for treatment decisions.