title: Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation.
abstract: ETV1 is overexpressed in a subset of clinical prostate cancers as a fusion transcript with many different partners. However, ETV1 can also be overexpressed as a full-length transcript. Full-length ETV1 protein functions differently from truncated ETV1 produced by fusion genes. In this study we describe the genetic background of full-length ETV1 overexpression and the biological properties of different full-length ETV1 isoforms in prostate cancer. Break-apart FISH showed in five out of six patient samples with overexpression of full-length ETV1 a genomic rearrangement of the gene, indicating frequent translocation. We were able to study the rearrangements in more detail in two tumors. In the first tumor 5'-RACE on cDNA showed linkage of the complete ETV1 transcript to the first exon of a prostate-specific two exon ncRNA gene that maps on chromosome 14 (EST14). This resulted in the expression of both full-length ETV1 transcripts and EST14-ETV1 fusion transcripts. In chromosome spreads of a xenograft derived from the second prostate cancer we observed a complex ETV1 translocation involving a chromosome 7 fragment that harbors ETV1 and fragments of chromosomes 4 and 10. Further studies revealed the overexpression of several different full-length transcripts, giving rise to four protein isoforms with different N-terminal regions. Even the shortest isoform synthesized by full-length ETV1 stimulated in vitro anchorage-independent growth of PNT2C2 prostate cells. This contrasts the lack of activity of even shorter N-truncated ETV1 produced by fusion transcripts. Our findings that in clinical prostate cancer overexpression of full-length ETV1 is due to genomic rearrangements involving different chromosomes and the identification of a shortened biologically active ETV1 isoform are highly relevant for understanding the mechanism of ETV1 function in prostate cancer.
authors.affiliation: Department of Pathology, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: Delila
authors.initials: D
authors.lastname: Gasi
authors.forename: Hetty A
authors.initials: HA
authors.lastname: van der Korput
authors.forename: Hannie C
authors.initials: HC
authors.lastname: Douben
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
authors.forename: Corrina M
authors.initials: CM
authors.lastname: de Ridder
authors.forename: Wytske M
authors.initials: WM
authors.lastname: van Weerden
authors.forename: Jan
authors.initials: J
authors.lastname: Trapman
mesh_terms: D002877:Chromosomes, Human; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D020033:Protein Isoforms; D012334:RNA, Neoplasm / Q000032:analysis*; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D020033:Protein Isoforms; D012334:RNA, Neoplasm; D014157:Transcription Factors