Distinct Genomic Aberrations Associated with TMPRSS2-ERG Fusion Prostate Cancer
F Demichelis, SR Setlur, R Beroukhim, S Perner, JO Korbel, C Lafargue, D Pflueger, C Pina, MD Hofer, A Sboner, MA Svensson, DS Rickman, M Meyerson, C Lee, MB Gerstein, R Kuefer, MA Rubin. Weill Cornell Medical College, New York, NY; Brigham and Women's Hospital, Boston, MA; Broad Institute of M.I.T. and Harvard, Cambridge, MA; Dana Farber Cancer Institute, Cambridge, MA; Yale University, New Haven, CT; University Hospital Ulm, Ulm, Germany
Background: Emerging molecular and clinical data suggest that ETS fusion prostate cancer (PCA) represents a distinct molecular subclass, driven most commonly by a hormonally regulated promoter and characterized by an aggressive natural history. The study of the genomic landscape of PCA in the light of ETS fusion events is required to understand the foundation of this distinct subtype.
Design: We performed a genome-wide DNA analysis on 49 PCA samples using Affymetrix 250K SNP arrays to explore for the presence of somatic genomic alterations We also analyzed transcript data for gene fusion enrichment. We further designed a high resolution NimbleGen tiling array to look for changes in the 27 ETS family members and to map genomic breakpoints for fusion.
Results: Twenty recurrent regions were detected, mainly occurring in the form of genomic loss. Co-occurring events included losses at 9q13.32 and 1p22.1. We discovered 3 genomic events associated with ETS fusion PCA, affecting chromosome arms 6q, 7q, and 16q and in addition, demonstrated consistent transcript deregulation. 6q genomic loss in non-fusion PCA is accompanied by gene expression deregulation in an independent dataset and by protein deregulation of MYO6. In order to analyze specific copy number alterations within the ETS genes, we performed a comprehensive analysis of all 27 ETS genes and of the deleted 3Mbp genomic area between ERG and TMPRSS2 (21q) for a set of PCA samples with an unprecedented resolution of 30 base pairs. We demonstrate that high resolution tiling arrays can be used to pin-point breakpoints leading to fusion events.
Conclusions: This study provides further support to defining a distinct molecular subtype of PCA based on the presence of ETS gene rearrangements.
Category: Special Category for 2009 - Pan-genomic/Pan-proteomic approaches to Cancer
Monday, March 9, 2009 2:15 PM
Platform Session: Section G, Monday Afternoon