N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer.
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.
Pflueger
Dorothee
D
Department of Pathology & Laboratory Medicine, Weill Cornell Medical College, New York, NY 10021, USA.
Rickman
David S
DS
Sboner
Andrea
A
Perner
Sven
S
LaFargue
Christopher J
CJ
Svensson
Maria A
MA
Moss
Benjamin J
BJ
Kitabayashi
Naoki
N
Pan
Yihang
Y
de la Taille
Alexandre
A
Kuefer
Rainer
R
Tewari
Ashutosh K
AK
Demichelis
Francesca
F
Chee
Mark S
MS
Gerstein
Mark B
MB
Rubin
Mark A
MA
D000726:Androgen Antagonists / Q000494:pharmacology; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005485:Flutamide / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000235:genetics*; D000071230:Transcriptional Regulator ERG; D000099259:N-myc Downstream-Regulated Gene 1 Protein
D000726:Androgen Antagonists; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004958:Estradiol; D004967:Estrogens; D005485:Flutamide; D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C072312:ERG protein, human; C515553:TMPRSS2-ERG fusion protein, human