The genomic complexity of primary human prostate cancer

Prostate cancer is the second most common cause of male cancer deaths in the United States. However, the full range of prostate cancer genomic alterations is incompletely characterized. Here we present the complete sequence of seven primary human prostate cancers and their paired normal counterparts. Several tumours contained complex chains of balanced (that is, ‘copy-neutral’) rearrangements that occurred within or adjacent to known cancer genes. Rearrangement breakpoints were enriched near open chromatin, androgen receptor and ERG DNA binding sites in the setting of the ETS gene fusion TMPRSS2–ERG, but inversely correlated with these regions in tumours lacking ETS fusions. This observation suggests a link between chromatin or transcriptional regulation and the genesis of genomic aberrations. Three tumours contained rearrangements that disrupted CADM2, and four harboured events disrupting either PTEN (unbalanced events), a prostate tumour suppressor, or MAGI2 (balanced events), a PTEN interacting protein not previously implicated in prostate tumorigenesis. Thus, genomic rearrangements may arise from transcriptional or chromatin aberrancies and engage prostate tumorigenic mechanisms.

[1]  Jie Zhang,et al.  Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer , 2009, Cell.

[2]  Arul M Chinnaiyan,et al.  TMPRSS2:ETV4 gene fusions define a third molecular subtype of prostate cancer. , 2006, Cancer research.

[3]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[4]  Jorma Isola,et al.  In vivo amplification of the androgen receptor gene and progression of human prostate cancer , 1995, Nature Genetics.

[5]  P. Kantoff,et al.  Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  L. Pearl,et al.  The Hsp90 molecular chaperone: an open and shut case for treatment. , 2008, The Biochemical journal.

[7]  J. Tchinda,et al.  Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. , 2006, Science.

[8]  Derek Y. Chiang,et al.  The landscape of somatic copy-number alteration across human cancers , 2010, Nature.

[9]  William R. Sellers,et al.  Phosphorylation of the PTEN Tail Acts as an Inhibitory Switch by Preventing Its Recruitment into a Protein Complex* , 2001, The Journal of Biological Chemistry.

[10]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[11]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[12]  Tom Royce,et al.  A comprehensive catalogue of somatic mutations from a human cancer genome , 2010, Nature.

[13]  Pier Paolo Pandolfi,et al.  Aberrant ERG expression cooperates with loss of PTEN to promote cancer progression in the prostate , 2009, Nature Genetics.

[14]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[15]  J. Eeckhoute,et al.  Unique ERalpha cistromes control cell type-specific gene regulation. , 2008, Molecular endocrinology.

[16]  Francesca Demichelis,et al.  Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma , 2010, Nature Medicine.

[17]  Martin J. Aryee,et al.  Androgen-induced TOP2B mediated double strand breaks and prostate cancer gene rearrangements , 2010, Nature Genetics.

[18]  S. Dhanasekaran,et al.  Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer , 2007, Nature.

[19]  A. Sparks,et al.  The mutation spectrum revealed by paired genome sequences from a lung cancer patient , 2010, Nature.

[20]  E. Olson,et al.  Association of Class II Histone Deacetylases with Heterochromatin Protein 1: Potential Role for Histone Methylation in Control of Muscle Differentiation , 2002, Molecular and Cellular Biology.

[21]  E. Birney,et al.  A small cell lung cancer genome reports complex tobacco exposure signatures , 2009, Nature.

[22]  Joshua F. McMichael,et al.  Genome Remodeling in a Basal-like Breast Cancer Metastasis and Xenograft , 2010, Nature.

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

[24]  J. Maguire,et al.  Integrative analysis of the melanoma transcriptome. , 2010, Genome research.

[25]  A. Børresen-Dale,et al.  COMPLEX LANDSCAPES OF SOMATIC REARRANGEMENT IN HUMAN BREAST CANCER GENOMES , 2009, Nature.

[26]  P. Deloukas,et al.  Signatures of mutation and selection in the cancer genome , 2010, Nature.

[27]  S. Varambally,et al.  Induced Chromosomal Proximity and Gene Fusions in Prostate Cancer , 2009, Science.

[28]  Ken Chen,et al.  Recurring mutations found by sequencing an acute myeloid leukemia genome. , 2009, The New England journal of medicine.

[29]  Cameron S. Osborne,et al.  Active genes dynamically colocalize to shared sites of ongoing transcription , 2004, Nature Genetics.

[30]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

[31]  C. Ross,et al.  Evidence for regulation of the PTEN tumor suppressor by a membrane-localized multi-PDZ domain containing scaffold protein MAGI-2. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Ben S. Wittner,et al.  Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1 , 2009, Nature.

[33]  D. Gordenin,et al.  Hypermutability of Damaged Single-Strand DNA Formed at Double-Strand Breaks and Uncapped Telomeres in Yeast Saccharomyces cerevisiae , 2008, PLoS genetics.

[34]  J. Eeckhoute,et al.  Unique ER Cistromes Control Cell Type-Specific Gene Regulation , 2008 .

[35]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[36]  S. H. Baek,et al.  BTB Domain-containing Speckle-type POZ Protein (SPOP) Serves as an Adaptor of Daxx for Ubiquitination by Cul3-based Ubiquitin Ligase* , 2006, Journal of Biological Chemistry.

[37]  H. Vogel,et al.  CHD5 Is a Tumor Suppressor at Human 1p36 , 2007, Cell.

[38]  I. Amit,et al.  Comprehensive mapping of long range interactions reveals folding principles of the human genome , 2011 .

[39]  P. Kantoff,et al.  Sipuleucel-T immunotherapy for castration-resistant prostate cancer. , 2010, The New England journal of medicine.

[40]  Jonathan W. Pillow,et al.  POSTER PRESENTATION Open Access , 2013 .

[41]  Mitch Dowsett,et al.  Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  S. Varambally,et al.  Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusions in prostate cancer. , 2008, Cancer research.

[43]  Daehee Hwang,et al.  Integrated Expression Profiling and ChIP-seq Analyses of the Growth Inhibition Response Program of the Androgen Receptor , 2009, PloS one.

[44]  R. Shah,et al.  Fluorescence in situ hybridization study shows association of PTEN deletion with ERG rearrangement during prostate cancer progression , 2009, Modern Pathology.

[45]  C. Sander,et al.  Cooperativity of TMPRSS2-ERG with PI3-kinase pathway activation in prostate oncogenesis , 2009, Nature Genetics.

[46]  Amy E. Hawkins,et al.  DNA sequencing of a cytogenetically normal acute myeloid leukemia genome , 2008, Nature.

[47]  J. Uhm.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2009 .

[48]  Ryan D. Morin,et al.  Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution , 2009, Nature.

[49]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[50]  Michael T. McManus,et al.  Chd1 regulates open chromatin and pluripotency of embryonic stem cells , 2009, Nature.

[51]  H. Scher,et al.  Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer , 2009, Science.

[52]  G. Parmigiani,et al.  The Consensus Coding Sequences of Human Breast and Colorectal Cancers , 2006, Science.

[53]  Zhaohui S. Qin,et al.  An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. , 2010, Cancer cell.