TY - JOUR
T1 - N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer
AU - Pflueger, Dorothee
AU - Rickman, David S.
AU - Sboner, Andrea
AU - Perner, Sven
AU - LaFargue, Christopher J.
AU - Svensson, Maria A.
AU - Moss, Benjamin J.
AU - Kitabayashi, Naoki
AU - Pan, Yihang
AU - De La Taille, Alexandre
AU - Kuefer, Rainer
AU - Tewari, Ashutosh K.
AU - Demichelis, Francesca
AU - Chee, Mark S.
AU - Gerstein, Mark B.
AU - Rubin, Mark A.
N1 - Funding Information:
Abbreviations: RT-PCR, reverse transcription–polymerase chain reaction; FISH, fluorescence in situ hybridization; RNA-seq, RNA sequencing; (b/a), break-apart Address all correspondence to: Mark A. Rubin, MD, Pathology and Laboratory Medicine, Weill Cornell Medical College, 1300 York Ave, Room C 410-A, New York, NY 10021. E-mail: [email protected] 1This work was supported by National Institutes of Health (NIH)/National Cancer Institute grant R01 CA125612 (M.A.R. and F.D.), Heinrich Warner Foundation (D.P.), Department of Defense grant PC61474 (S.P.), and NIH/National Human Genome Research Institute (NHGRI) grant R44HG004237 (M.S.C.). The authors thank the support of the “Yale University Biomedical High Performance Computing Center” and NIH grant no. RR19895 that funded the computer cluster instrumentation. 2This article refers to supplementary materials, which are designated by Tables W1 to W4 and Figures W1 to W5 and are available online at www.neoplasia.com. 3These authors contributed equally to this work. Received 3 April 2009; Revised 16 May 2009; Accepted 20 May 2009 Copyright © 2009 Neoplasia Press, Inc. All rights reserved 1522-8002/09/$25.00 DOI 10.1593/neo.09572
PY - 2009/8
Y1 - 2009/8
N2 - A step toward the molecular classification of prostate cancer was the discovery of recurrent erythroblast transformation-specific rearrangements, most commonly fusing the androgen-regulated TMPRSS2 promoter to ERG. The TMPRSS2-ERG fusion is observed in around 90% of tumors that overexpress the oncogene ERG. The goal of the current study was to complete the characterization of these ERG-overexpressing prostate cancers. Using fluorescence in situ hybridization and reverse transcription-polymerase chain reaction assays, we screened 101 prostate cancers, identifying 34 cases (34%) with the TMPRSS2-ERG fusion. Seven cases demonstrated ERG rearrangement by fluorescence in situ hybridization without the presence of TMPRSS2-ERG fusion messenger RNA transcripts. Screening for known 5′ partners, we determined that three cases harbored the SLC45A3-ERG fusion. To discover novel 5′ partners in these ERG-overexpressing and ERG-rearranged cases, we used paired-end RNA sequencing. We first confirmed the utility of this approach by identifying the TMPRSS2-ERG fusion in a known positive prostate cancer case and then discovered a novel fusion involving the androgen-inducible tumor suppressor, NDRG1 (N-myc downstream regulated gene 1), and ERG in two cases. Unlike TMPRSS2-ERG and SCL45A3-ERG fusions, the NDRG1-ERG fusion is predicted to encode a chimeric protein. Like TMPRSS2, SCL45A3 and NDRG1 are inducible not only by androgen but also by estrogen. This study demonstrates that most ERG-overexpressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions. Broader implications of this study support the use of RNA sequencing to discover novel cancer translocations.
AB - A step toward the molecular classification of prostate cancer was the discovery of recurrent erythroblast transformation-specific rearrangements, most commonly fusing the androgen-regulated TMPRSS2 promoter to ERG. The TMPRSS2-ERG fusion is observed in around 90% of tumors that overexpress the oncogene ERG. The goal of the current study was to complete the characterization of these ERG-overexpressing prostate cancers. Using fluorescence in situ hybridization and reverse transcription-polymerase chain reaction assays, we screened 101 prostate cancers, identifying 34 cases (34%) with the TMPRSS2-ERG fusion. Seven cases demonstrated ERG rearrangement by fluorescence in situ hybridization without the presence of TMPRSS2-ERG fusion messenger RNA transcripts. Screening for known 5′ partners, we determined that three cases harbored the SLC45A3-ERG fusion. To discover novel 5′ partners in these ERG-overexpressing and ERG-rearranged cases, we used paired-end RNA sequencing. We first confirmed the utility of this approach by identifying the TMPRSS2-ERG fusion in a known positive prostate cancer case and then discovered a novel fusion involving the androgen-inducible tumor suppressor, NDRG1 (N-myc downstream regulated gene 1), and ERG in two cases. Unlike TMPRSS2-ERG and SCL45A3-ERG fusions, the NDRG1-ERG fusion is predicted to encode a chimeric protein. Like TMPRSS2, SCL45A3 and NDRG1 are inducible not only by androgen but also by estrogen. This study demonstrates that most ERG-overexpressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions. Broader implications of this study support the use of RNA sequencing to discover novel cancer translocations.
UR - https://www.scopus.com/pages/publications/67650489112
U2 - 10.1593/neo.09572
DO - 10.1593/neo.09572
M3 - Article
C2 - 19649210
AN - SCOPUS:67650489112
SN - 1522-8002
VL - 11
SP - 804
EP - 811
JO - Neoplasia
JF - Neoplasia
IS - 8
ER -