Bioinformatics approach leads to the discovery of the TMPRSS2:ETS gene fusion in prostate cancer.
Recurrent chromosomal rearrangements have not been well characterized in common carcinomas. We describe the use of a novel bioinformatics approach to discover candidate oncogenic chromosomal aberrations on the basis of outlier gene expression called COPA (cancer outlier profile analysis). We demonstrate how this approach led to the identification of gene fusions of the 5'-untranslated region of TMPRSS2 (21q22.3), an androgen regulated gene, with the ETS transcription factor family members, either ERG (21q22.2), ETV1 (7p21.2), or ETV4(17q21). These novel gene fusions suggest a mechanism for overexpression of the ETS genes in the majority of prostate cancers identified through PSA screening. Considering the high incidence of prostate cancer and the high frequency of this gene fusion, the TMPRSS2-ETS gene fusions are the most common genetic aberration so far described in human malignancies. The clinical implications of this discovery are significant for diagnosis and potentially for the development of targeted therapy.
Rubin
Mark A
MA
Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02115-6110, USA. marubin@partners.org.or
Chinnaiyan
Arul M
AM
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D019295:Computational Biology / Q000379:methods*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D050939:Gene Fusion; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012697:Serine Endopeptidases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; D015514:Oncogene Proteins, Fusion; C529660:TMPRSS2-ETS fusion protein, human; D014157:Transcription Factors; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human