MP49-07 THE ANDROGEN RECEPTOR IS A DRIVER OF DNA BREAKPOINTS AND FUSION EVENTS IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research IV1 Apr 2014MP49-07 THE ANDROGEN RECEPTOR IS A DRIVER OF DNA BREAKPOINTS AND FUSION EVENTS IN PROSTATE CANCER Matthew Hong, Geoff Macintyre, Niall Corcoran, Clare Sloggett, Haroon Naeem, Marek Cmero, John Pedersen, Izhak Haviv, Andrew Ryan, Pramit Phal, Anthony Costello, and Christopher Hovens Matthew HongMatthew Hong More articles by this author , Geoff MacintyreGeoff Macintyre More articles by this author , Niall CorcoranNiall Corcoran More articles by this author , Clare SloggettClare Sloggett More articles by this author , Haroon NaeemHaroon Naeem More articles by this author , Marek CmeroMarek Cmero More articles by this author , John PedersenJohn Pedersen More articles by this author , Izhak HavivIzhak Haviv More articles by this author , Andrew RyanAndrew Ryan More articles by this author , Pramit PhalPramit Phal More articles by this author , Anthony CostelloAnthony Costello More articles by this author , and Christopher HovensChristopher Hovens More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1108AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail Introduction and Objectives The TMPRSS2-ERG fusion is the most well-known fusion event in prostate cancer. Since specific fusion genes are associated with specific tumour types, it is likely that tissue-specific mechanisms underlie the formation of structural rearrangements in cancer genomes. Recent studies have suggested that androgen receptor (AR) may play a role in the formation of TMPRSS2-ERG fusions, bringing the two loci in close proximity in the nucleus and facilitating DNA strand break and repair along with AR associated enzymes. To explore this mechanism more comprehensively, we performed whole genome sequencing on 14 prostate cancer samples from 7 patients. Methods Fresh frozen prostate cancer samples were taken from patients undergoing radical prostatectomy or biopsy. Tissue samples were cryosectioned and tumour content confirmed by a pathologist prior to mechanical homogenisation and simultaneous DNA and RNA extraction (Allprep Micro Kit, Qiagen). Whole genome sequencing was performed to 40x coverage on the Illumina HiSeq2000 platform. Results Across the 14 cancer genomes we identified a base-pair resolution high confidence set of 2,921 structural variations (some recurrent) at an average of 209 per sample and found that a large proportion of these breakpoints were in close proximity to curated androgen receptor binding sites from high-confidence ChIP-Seq data. Furthermore, when we examined breakpoints in genome datasets from 11 other cancers from the TCGA and ICGC projects, we identified a similar association with androgen (and estrogen) receptor binding sites specifically in hormone-dependent tumour types including prostate, breast, squamous cell lung, and ovarian cancers, but no such correlation in glioblastoma, renal, lung, colon or lymphoma genome datasets. Conclusions These data suggest that the androgen receptor drives genome wide breakpoints and novel fusion events in prostate cancer and potentially serves to explain why androgen exposure is necessary for prostate cancer development. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e504 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Matthew Hong More articles by this author Geoff Macintyre More articles by this author Niall Corcoran More articles by this author Clare Sloggett More articles by this author Haroon Naeem More articles by this author Marek Cmero More articles by this author John Pedersen More articles by this author Izhak Haviv More articles by this author Andrew Ryan More articles by this author Pramit Phal More articles by this author Anthony Costello More articles by this author Christopher Hovens More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...