Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Whole Genome Methylation Analysis of Metastatic Castration Resistant Prostate Cancer

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Terence Friedlander

PROVIDER: E-GEOD-34174 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Characterization of the prostate cancer transcriptome and genome has identified chromosomal rearrangements and copy number gains/losses, including ETS gene fusions, PTEN loss and androgen receptor (AR) amplification, that drive prostate cancer development and progression to lethal, metastatic castrate resistant prostate cancer (CRPC)1. As less is known about the role of mutations2-4, here we sequenced the exomes of 50 lethal, heavily-pretreated metastatic CRPCs obtained at rapid autopsy (including three different foci from the same patient) and 11 treatment naïve, high-grade localized prostate cancers. We identified low overall mutation rates even in heavily treated CRPC (2.00/Mb) and confirmed the monoclonal origin of lethal CRPC. Integrating exome copy number analysis identified disruptions of CHD1, which define a subtype of ETS? prostate cancer. Similarly, we demonstrate that ETS2, which is deleted in ~1/3 of CRPCs (commonly through TMPRSS2:ERG fusions), is a prostate cancer tumor suppressor that can also be deregulated through mutation. Further, we identified recurrent mutations in multiple chromatin/histone modifying genes, including MLL2 (mutated in 8.6% of prostate cancers), and demonstrate interaction of the MLL complex with AR, which is required for AR mediated signaling. We also identified novel recurrent mutations in the AR collaborating factor FOXA1, which is mutated in 5 of 147 (3.4%) prostate cancers (both untreated localized prostate cancer and CRPC) , and showed that mutated FOXA1 represses androgen signaling and increases tumor growth in vitro and in vivo. Proteins that physically interact with AR, such as the ERG gene fusion product, FOXA1, MLL2, UTX, and ASXL1 were found to be mutated in CRPC, suggesting novel drivers of prostate cancer progression and potential resistance mechanisms to anti-androgen therapies. In summary, we describe the mutational landscape of a heavily treated metastatic cancer, identify novel mechanisms of AR signaling deregulated in prostate cancer, and prioritize candidates for future study. Gene expression profiling and array CGH (aCGH) was performed on matched benign prostate tissues (n=28), localized prostate cancer (n=59), and metastatic castrate resistant prostate cancer (CRPC, n=35). For gene expression profiling, frozen prostate tissue samples (channel 2), were hybridized against a commercial pool of benign prostate tissue (Clontech, channel 1). For aCGH, frozen prostate tissue samples (channel 2) were hybridized against a commerical sample of Human Male Genomic DNA (Promega, channel 1).

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Whole Genome Methylation Analysis of Metastatic Castration Resistant Prostate Cancer

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