N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer

Dorothee Pflueger, David S Rickman, Andrea Sboner, Sven Perner, Christopher J LaFargue, Maria A Svensson, Benjamin J Moss, Naoki Kitabayashi, Yihang Pan, Alexandre de la Taille, Rainer Kuefer, Ashutosh K Tewari, Francesca Demichelis, Mark S Chee, Mark B Gerstein and Mark A Rubin

Year 2009, Volume 11, Issue 8

Abstract

A step towards the molecular classification of prostate cancer was the discovery of recurrent ETS rearrangements, most commonly fusing the androgen-regulated TMPRSS2 promoter to ERG. The TMPRSS2-ERG fusion is observed in around 90% of tumors that over-express the oncogene ERG. The goal of the current study was to complete the characterization of these ERG over-expressing prostate cancers. Using fluorescent in-situ hybridization (FISH) and RT-PCR assays, we screened 101 prostate cancers, identifying 34 (34%) cases with the TMPRSS2-ERG fusion. Seven cases demonstrated ERG rearrangement by FISH without the presence of TMPRSS2-ERG fusion mRNA transcripts. Screening for known 5’ partners, we determined that 3 cases harbored the SLC45A3-ERG fusion. To discover novel 5’ partners in these ERG over-expressing and ERG rearranged cases, we used paired-end RNA-sequencing (RNA-seq). 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 by androgen but also by estrogen. This study demonstrates that the vast majority of ERG over-expressing prostate cancers harbor hormonally regulated TMPRSS2-ERG, SLC45A3-ERG, or NDRG1-ERG fusions. Broader implications of this study support the use of RNA-seq to discover novel cancer translocations.

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