Abstract 2743: Accelerating the exploration of novel gene fusion events in prostate cancer

Abstract

Abstract Gene fusions are regarded as cancer defining and often proven causative for cancer development. Up to 50% of prostate cancers harbor recurrent gene fusions, most often the TMPRSS2-ERG fusion. Other ETS gene fusions have been described involving ETV1, ETV4, and ETV5. The remaining prostate cancers are considered gene fusion negative based on fluorescence in-situ hybridization (FISH) or RT-PCR for known fusion specific transcripts. Paired-end RNA-sequencing is a novel approach to systematically interrogate for fusion transcripts in a global and un-biased manner. Herein, we exploit FusionSeq, a computational tool specifically developed to nominate chimeric transcripts from paired-end RNA-seq data, with the goal of identifying new gene fusions. Using FusionSeq we identified the androgen-induced genes FKBP5 and KLK2 as two novel 5′ fusion partners for the ETS genes ERG and ETV1, respectively. General transcriptional chimerism (e.g. read-through transcripts) without evidence of underlying genomic rearrangements is not restricted to prostate cancer but also occurs in the patient's matched benign prostate tissue, providing evidence for an extended complexity of the cellular transcriptome and supporting the notion that a gene's definition might have to be considered flexible. Finally, we report the identification and the validation of two novel gene fusions: i) the tumor suppressor and cell cycle regulator CDKN1A (p21WAF, CIP1) is fused to CD9; besides down-regulating p21 gene expression, the CDKN1A-CD9 fusion also alters the CD9 protein. ii) by fusing IKBKB (IKK2, IκB kinase beta subunit) to TNPO1 (transportin 1), IKBKB gene expression increases over other prostate cancers, suggesting a pronounced activation of the NFκB complex. Our results show that a small subset of prostate cancers may harbor private gene fusions involving tumor suppressors and regulators of pathways implicated in cancer development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2743.