title: Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.
abstract: Progression of primary prostate cancer to castration-resistant prostate cancer (CRPC) is associated with numerous genetic and epigenetic alterations that are thought to promote survival at metastatic sites. In this study, we investigated gene copy number and CpG methylation status in CRPC to gain insight into specific pathophysiologic pathways that are active in this advanced form of prostate cancer. Our analysis defined and validated 495 genes exhibiting significant differences in CRPC in gene copy number, including gains in androgen receptor (AR) and losses of PTEN and retinoblastoma 1 (RB1). Significant copy number differences existed between tumors with or without AR gene amplification, including a common loss of AR repressors in AR-unamplified tumors. Simultaneous gene methylation and allelic deletion occurred frequently in RB1 and HSD17B2, the latter of which is involved in testosterone metabolism. Lastly, genomic DNA from most CRPC was hypermethylated compared with benign prostate tissue. Our findings establish a comprehensive methylation signature that couples epigenomic and structural analyses, thereby offering insights into the genomic alterations in CRPC that are associated with a circumvention of hormonal therapy. Genes identified in this integrated genomic study point to new drug targets in CRPC, an incurable disease state which remains the chief therapeutic challenge.
authors.affiliation: Division on Genitourinary Medical Oncology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA.
authors.forename: Terence W
authors.initials: TW
authors.lastname: Friedlander
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.forename: Scott A
authors.initials: SA
authors.lastname: Tomlins
authors.forename: Vy T
authors.initials: VT
authors.lastname: Ngo
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Aruna
authors.initials: A
authors.lastname: Azameera
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Pienta
authors.forename: Arul
authors.initials: A
authors.lastname: Chinnaiyan
authors.forename: Michael M
authors.initials: MM
authors.lastname: Ittmann
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Ryan
authors.forename: Pamela L
authors.initials: PL
authors.lastname: Paris
mesh_terms: D001344:Autopsy; D016000:Cluster Analysis; D055028:Comparative Genomic Hybridization; D018899:CpG Islands / Q000235:genetics; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D057890:Epigenomics; D004960:Estradiol Dehydrogenases / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D009919:Orchiectomy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics; D013739:Testosterone / Q000378:metabolism
chemical_list: C410798:AR protein, human; D011944:Receptors, Androgen; D016160:Retinoblastoma Protein; D013739:Testosterone; D004960:Estradiol Dehydrogenases; C523763:HSD17B2 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human