Discovery and Characterization of Recurrent Gene Fusions in Prostate Cancer.

Recurrent chromosomal rearrangements have been well characterized in hematologic and mesenchymal malignancies, but not in common carcinomas. A novel bioinformatics algorithm termed Cancer Outlier Profile Analysis (COPA) was developed to analyze DNA microarray data for genes markedly over-expressed (“outliers”) in a subset of cases. COPA identified the ETS family members ERG and ETV1 as high-ranking outliers in multiple prostate cancer profiling studies. In cases with outlier expression of ERG or ETV1, recurrent gene fusions of the 5’ untranslated region of the prostate-specific, androgen-induced gene TMPRSS2 to the respective ETS family member were identified. In vitro studies in cancer cell lines demonstrated that androgen-responsive promoter elements of TMPRSS2 mediate the aberrant ETS family member over-expression. Subsequent interrogation of all ETS family members in prostate cancer profiling studies identified outlier expression of ETV4 in two of 98 cases. In one such case, ETV4 over-expression was confirmed and a fusion of the TMPRSS2 and ETV4 loci was identified. A large scale profiling and integrated molecular concepts analysis demonstrated that ETS rearrangement-positive and -negative tumors have distinct transcriptional programs, with loss at 6q21 as a possible defining genetic event in ETS negative prostate cancers. While TMPRSS2:ERG fusions are predominant, fewer TMPRSS2:ETV1 cases were identified than would be expected based on the frequency of ETV1 outlier expression. Through characterizing additional ETV1 outlier cases, novel 5’ fusion partners defining distinct functional classes of ETS gene rearrangements were identified. These include fusions involving androgen-stimulated, androgen-repressed and androgen-insensitive 5’ partners. As the commonality of ETS rearrangements is aberrant over-expression, in vitro and in vivo recapitulation demonstrated that ETV1 or ERG over-expression in benign prostate cells and the mouse prostate confers neoplastic phenotypes. Together, this work suggests a pathogenetically important role for recurrent chromosomal rearrangements in a common epithelial tumor and has important implications in the molecular diagnosis and treatment of prostate cancer. Deregulation of ETS family member expression through gene fusions appears to be a generalized mechanism for prostate cancer development in the majority of cases. Additionally, other common epithelial tumors may be driven by uncharacterized gene rearrangements.Ph.D.Molecular & Cellular PathologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/57601/2/tomlinss_1.pd