Data to reproduce analysis in the WCDT metastatic prostate tumor subtypying paper

Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation AR-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration resistant prostate cancer (mCRPC), defined by whether the tumor expresses either AR or neuroendocrine markers. Among the subtypes of mCRPC, the molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterize genomic and epigenomic features of treatment-emergent mCRPC subtypes in 210 tumors by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing. We show that AR-/NE- tumors exhibit a clinically and molecularly distinct phenotype. Patients with AR-/NE- mCRPC tumors have the shortest survival, and these tumors preferentially harbor amplification of the chromatin remodeler <em>CHD7</em> and loss of <em>PTEN</em>. We demonstrate that methylation changes in <em>CHD7</em> candidate enhancers are linked to elevated <em>CHD7</em> expression in AR-/NE+ tumors. Moreover, we use genome-wide methylation analysis to nominate the Krüppel-like factor gene <em>KLF5</em> as a driver of the AR-/NE- phenotype and link its activity to loss of the tumor supressor <em>RB1</em>. These observations reveal the aggressiveness of the AR-/NE- tumors and elucidate genomic and epigenomic drivers of mCRPC subtypes, which may facilitate the identification of novel therapeutic targets in this highly aggressive disease.