FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer

Abstract

To characterize the pattern of ETS rearrangements and to uncover novel ETS fusion genes, we analyzed 200 prostate carcinomas (PCa) with TaqMan low-density arrays (TLDAs), followed by selective analyses with fluorescence in situ hybridization (FISH), RT-PCR, and sequencing. Besides confirming the recurrent presence of ERG, ETV1, ETV4, and ETV5 rearrangements, we here report FLI1 as the fifth ETS transcription factor involved in fusion genes in prostate cancer. Outlier expression of the FLI1 gene was detected by TLDAs in one PCa that showed relative overexpression of FLI1 exons 4:5 as compared with FLI1 exons 2:3. A structural rearrangement was found using FISH probes flanking the FLI1 gene and RT-PCR and sequencing analyses showed fusion of SLC45A3 exon 1 with FLI1 exon 3. Interestingly, we found four cases with two different ETS rearrangements in the index tumor, thus revealing intratumor genetic heterogeneity. Correlation analysis with clinico-pathological data showed association of ERG rearrangements with locally advanced disease (pT3, P = 0.007) and MYC overexpression (P = 0.001), and association of ETV1 rearrangements with PTEN downregulation (P = 0.015). We report that FLI1 is a novel ETS transcription factor involved in gene fusions in prostate cancer and that intratumor genetic heterogeneity of ETS rearrangements can occasionally be found in index primary tumors.