The comprehensive methylation landscape of metastatic castration-resistant prostate cancer (mCRPC) identifies new phenotypic subtypes: Results from the West Coast Prostate Cancer Dream Team (WCDT).

Abstract

5507 Background: While recent studies have delineated the genomic landscape of mCRPC, its epigenomic landscape has not been as well characterized. The goal of this study was to define the comprehensive methylation landscape of mCRPC. Methods: mCRPC patients (pts) underwent a metastasis biopsy as part of a multi-institutional study (NCT02432001). Deep whole-genome bisulfite sequencing (mean depth 46x) was performed on fresh frozen tissue from 100 mCRPC patients; data was paired with deep whole-genome and transcriptome sequencing from the same samples. Unbiased hierarchical clustering of the mCRPC methylome was undertaken, and the survival of patients in each cluster was calculated using the Kaplan Meier method. Results: Unbiased hierarchical clustering revealed several distinct subtypes. 22% of mCRPC samples exhibited a novel epigenomic subtype associated with hyper-methylation. This hypermethylated (HM) cluster was significantly associated with somatic mutations in genes known to be involved in methylation, eg TET2 and DNMT3B, as well as in genes in which mutations have been associated with hyper-methylation in other cancer types ( IDH1 in glioblastoma and BRAF in colon cancer). mCRPC survival was 56.1 mos in pts with HM cancers compared to 35.6 mos in non-HM (p = .055). Methylome clustering also identified a unique cluster comprised of all patients with treatment-induced small cell/neuroendocrine cancer, a subtype previously associated with poor survival. Conclusions: This integrated study of whole-genome, whole methylome and whole-transcriptome sequencing provides the first comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer, and has identified at least two distinct subtypes. The clinical and therapeutic implications of methylation subtypes should be explored in future studies. Clinical trial information: NCT02432001 .