Identification of gene copy number and whole-genome methylation changes associated with lethal metastatic castration-resistant prostate cancer (CRPC)

6 Background: Metastatic CRPC undergoes significant genomic evolution compared to primary, localized disease. Multiple genetic mechanisms contribute to this evolution including changes in gene copy number as well as and changes in CpG island methylation. In this study, copy number and methylation status of metastatic CRPC tissue obtained at autopsy were assessed by high-resolution array comparative genomic hybridization (aCGH) and whole genome methylation microarray profiling. Methods: Array CGH was performed on DNA isolated from metastatic CRPC samples obtained from the University of Michigan Rapid Autopsy Program, using the Agilent Human Genome 244K CGH Microarray. A total of 15 samples comprising 7 metastatic liver implants and 8 soft tissue metastases were analyzed with DNA Analytics 4.0 software. Expression of genes identified as commonly amplified or deleted was assessed in a confirmatory fashion using existing Agilent 4×44 Expression Array data. The Illumina Infinium HumanMethylation27 BeadChip was used to determine whole genome methylation status. Results: A total of 79 amplified and 419 deleted genes common to >66% of samples were identified. There was significant correlation (p85% of samples, suggesting that inactivation of this tumor suppressor through multiple pathways is critical to tumor cell survival. Conclusions: This is the first known study examining both gene copy number and whole genome CpG island methylation status in metastatic CRPC. Integration of this data allows for identification of specific genes or pathways that confer a selective growth advantage to prostate cancer cells harboring those changes. No significant financial relationships to disclose.