Whole Genome Methylation Analysis of Metastatic Castration Resistant Prostate Cancer

Relatively little is known about how changes in gene copy number (CN) and gene CpG methylation interact to affect specific pathways in metastatic castration-resistant prostate cancer (CRPC). Oligonucleotide array comparative genomic hybridization (aCGH) was performed on DNA isolated from 15 metastatic CRPC samples. Commonly aberrant genes were evaluated in a confirmatory fashion using PCR, aCGH data from primary tumors, and existing CRPC expression data. Array-based comprehensive CpG methylation was assessed on the same sample set. A total of 495 genes (79 gained, 416 deleted) were CN aberrant in ≥66% of the samples by aCGH, and 77 (9 amplified, 68 deleted) had statistically concordant expression including gain of AR and loss of PTEN and RB1. Significant CN differences were seen between the genomes of patients with AR-amplified and AR-unamplified tumors, including common loss of AR repressors in AR-unamplified tumors. The majority of CRPC samples were hypermethylated compared to benign prostate tissue. Simultaneous methylation and heterozygous gene deletion occurred in the tumor suppressor RB1 and in HSD17B2, responsible for testosterone metabolism. Establishment of a comprehensive methylation signature and coupling of epigenomic and structural analyses sheds light on the alterations that allow CRPC to circumvent hormonal therapy and may provide new drug targets for what is currently an incurable disease state. 15 tumor samples taken from 14 men with metastatic castration resistant prostate cancer were analyzed, including two samples from the same patient. No control samples were used for this experiment.