ORLANDO, FL USA (UroToday.com) - CRPC is an evolution of genetic and epigenetic events. Genetic alterations include alterations in gene copy number and changes in CpG island methylation. These investigators studied copy number and methylation status of metastatic CRPC tissue obtained at autopsy. The data was obtained by high-resolution array comparative genomic hybridization (aCGH) and whole genome methylation microarray profiling.
Metastatic CRPC autopsy samples were obtained from the University of Michigan Rapid Autopsy Program. Array CGH was performed on DNA using the Agilent Human Genome 244K CGH Microarray. A total of 15 samples from 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 4x44 Expression Array data. The investigators used the Illumina Infinium HumanMethylation27 BeadChip to determine whole genome methylation status.
They found 79 amplified and 419 deleted genes common to >66% of samples. There was significant correlation of gene copy number to mRNA level for 9 of the amplified and 76 of the deleted genes. This included amplification or overexpression of AR and deletion or underexpression of tumor suppressor genes PTEN and RB. Copy number for androgen synthetic genes CYP17A1, HSD17B3, HSD17B4, and HSD3B2 was normal. However, methylation analysis indicated that they were upregulation in the majority of samples, thus suggesting an alternative mechanism of intra-tumoral hormone production. Promoter hypermethylation and gene deletion of RB1 was detected in >85% of samples. This suggests that inactivation of RB1 through multiple pathways is important to tumor cell survival. These data facilitate identification of specific genes or pathways that provide a selective growth advantage to prostate tumors harboring those changes.
Presented by Terence W. Friedlander, MD at the 2011 Genitourinary Cancers Symposium, General Poster Session B: Prostate Cancer - February 17-19, 2011 - Orlando World Center Marriott, Orlando, Florida USA