title: 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.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Paulo
authors.forename: João D
authors.initials: JD
authors.lastname: Barros-Silva
authors.forename: Franclim R
authors.initials: FR
authors.lastname: Ribeiro
authors.forename: João
authors.initials: J
authors.lastname: Ramalho-Carvalho
authors.forename: Carmen
authors.initials: C
authors.lastname: Jerónimo
authors.forename: Rui
authors.initials: R
authors.lastname: Henrique
authors.forename: Guro E
authors.initials: GE
authors.lastname: Lind
authors.forename: Rolf I
authors.initials: RI
authors.lastname: Skotheim
authors.forename: Ragnhild A
authors.initials: RA
authors.lastname: Lothe
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons; D015321:Gene Rearrangement; D018740:Genetic Heterogeneity; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009004:Monosaccharide Transport Proteins; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D050596:Oncogene Fusion; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: D004268:DNA-Binding Proteins; C072312:ERG protein, human; C095239:ETV1 protein, human; C078433:FLI1 protein, human; D026901:Membrane Transport Proteins; D009004:Monosaccharide Transport Proteins; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; C551031:SLC45a3 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071230:Transcriptional Regulator ERG