Common structural and epigenetic changes in the genome of castration-resistant prostate cancer.

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.

[1]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[2]  Allen D. Delaney,et al.  Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters , 2010, Nature.

[3]  D. Dearnaley,et al.  Significant and sustained antitumor activity in post-docetaxel, castration-resistant prostate cancer with the CYP17 inhibitor abiraterone acetate. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  P. Kantoff,et al.  Phase I clinical trial of the CYP17 inhibitor abiraterone acetate demonstrating clinical activity in patients with castration-resistant prostate cancer who received prior ketoconazole therapy. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  Anushya Muruganujan,et al.  PANTHER version 7: improved phylogenetic trees, orthologs and collaboration with the Gene Ontology Consortium , 2009, Nucleic Acids Res..

[6]  K. Gunderson,et al.  Genome-wide DNA methylation profiling using Infinium® assay. , 2009, Epigenomics.

[7]  D. Wilson.  Tissue , 2009, The Lancet.

[8]  Jun Luo,et al.  Copy Number Analysis Indicates Monoclonal Origin of Lethal Metastatic Prostate Cancer , 2009, Nature Medicine.

[9]  R. Vessella,et al.  Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. , 2009, Cancer research.

[10]  John T. Wei,et al.  The role of SPINK1 in ETS rearrangement-negative prostate cancers. , 2008, Cancer cell.

[11]  P. Nelson,et al.  Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. , 2008, Cancer research.

[12]  R. Shah,et al.  CHARACTERIZATION OF TMPRSS2-ETS GENE ABERRATIONS IN ANDROGEN INDEPENDENT METASTATIC PROSTATE CANCER , 2008 .

[13]  P. Nelson,et al.  Intracrine androgen metabolism in prostate cancer progression: mechanisms of castration resistance and therapeutic implications. , 2008, Best practice & research. Clinical endocrinology & metabolism.

[14]  D. Tindall,et al.  Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. , 2007, Endocrine reviews.

[15]  Anya Tsalenko,et al.  High resolution oligonucleotide CGH using DNA from archived prostate tissue , 2007, The Prostate.

[16]  Klaus Jung,et al.  Discovery and validation of 3 novel DNA methylation markers of prostate cancer prognosis. , 2007, The Journal of urology.

[17]  Yusuke Nakamura,et al.  Molecular features of hormone-refractory prostate cancer cells by genome-wide gene expression profiles. , 2007, Cancer research.

[18]  A. Riggs,et al.  Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay , 2007, Proceedings of the National Academy of Sciences.

[19]  Tapio Visakorpi,et al.  Genetic aberrations in prostate cancer by microarray analysis , 2006, International journal of cancer.

[20]  T. Golub,et al.  Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. , 2006, Cancer research.

[21]  W. Sellers,et al.  Akt-regulated pathways in prostate cancer , 2005, Oncogene.

[22]  C. Iacobuzio-Donahue,et al.  Immortalizing the complexity of cancer metastasis: Genetic features of lethal metastatic pancreatic cancer obtained from rapid autopsy , 2005, Cancer biology & therapy.

[23]  Dennis B. Troup,et al.  NCBI GEO: mining millions of expression profiles—database and tools , 2004, Nucleic Acids Res..

[24]  Gordon K. Smyth,et al.  limma: Linear Models for Microarray Data , 2005 .

[25]  Jane Fridlyand,et al.  Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors. , 2005, Human molecular genetics.

[26]  E. Diamandis,et al.  The emerging roles of human tissue kallikreins in cancer , 2004, Nature Reviews Cancer.

[27]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[28]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[29]  G. Rodan,et al.  The LATS2/KPM tumor suppressor is a negative regulator of the androgen receptor. , 2004, Molecular endocrinology.

[30]  John D. Storey.  The positive false discovery rate: a Bayesian interpretation and the q-value , 2003 .

[31]  M. Campbell,et al.  PANTHER: a library of protein families and subfamilies indexed by function. , 2003, Genome research.

[32]  Hubert Vesselle,et al.  Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. , 2003, Human pathology.

[33]  Alicia Samuels,et al.  Cancer Statistics, 2003 , 2003, CA: a cancer journal for clinicians.

[34]  Anushya Muruganujan,et al.  PANTHER: a browsable database of gene products organized by biological function, using curated protein family and subfamily classification , 2003, Nucleic Acids Res..

[35]  E. Gelmann,et al.  Molecular biology of the androgen receptor. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  W. Reik,et al.  An intragenic methylated region in the imprinted Igf2 gene augments transcription , 2001, EMBO reports.

[37]  F. Ghadessy,et al.  Human androgen receptor mutation disrupts ternary interactions between ligand, receptor domains, and the coactivator TIF2 (transcription intermediary factor 2). , 2000, Molecular endocrinology.

[38]  K. Pienta,et al.  Rapid ("warm") autopsy study for procurement of metastatic prostate cancer. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  Shih-Ming Huang,et al.  Mouse Zac1, a Transcriptional Coactivator and Repressor for Nuclear Receptors , 2000, Molecular and Cellular Biology.

[40]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[41]  J. Costello,et al.  Graded methylation in the promoter and body of the O6-methylguanine DNA methyltransferase (MGMT) gene correlates with MGMT expression in human glioma cells. , 1994, The Journal of biological chemistry.