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Purpose of the study: This study was conducted to define the role of Dachshund in prostate cancer, through assessing human prostate cancer samples and through genetic deletion in the mouse. Prostate cancer (PCa), the second leading cause of death in American men, is a genetically heterogeneous disease, likely representing distinct genetic drivers, with terminal events caused primarily by metastasis. Substratification of PCa into genetic subtypes, forms the basis of rational therapy for PCa. A better molecular understanding of the disease is necessary in order to develop novel targeted therapies of metastatic PCa. Known genetic drivers to tumor initiation include PTEN and NKX3.1 deletions, rearrangements of the TMPRSS2 gene to the oncogenic ETS transcription factor, ERG, and genetic predisposing factors include germline DNA-repair gene mutations. The DACH1 gene, initially cloned as an inhibitor of Elipse, the hyperactive epidermal growth factor (EGFR) in Drosophila, was found to be reduced in abundance in several malignancies including breast and prostate cancer. Results: In order to determine whether the DACH1 gene is deleted or mutated in prostate cancer we interrogated the genomic sequencing analysis of over 490 patients from 5 population cohorts. Homozygous deletion of DACH1 was identified in 18% (N=61), 11% (N=136), 10% (N=492), 7% (N=103) and 3% (N=150) of prostate cancer in 5 distinct cohorts. The prevalence of DACH1 gene deep deletions was higher in the metastasis than in the primary tumors. The Transgenic Adenocarcinoma Mouse Prostate (TRAMP) transgenic, Dach1fl/fl, and Probasin-Cre, ROSA26mT/mG transgenic mice were used to generate a prostate epithelial cell specific Dach1 gene knockout mouse (Probasin-Cre-Dach1fl/fl ROSA26mT/mG-TRAMP) lines. Prostate specific deletion of the murine Dach1 gene enhanced progression of prostatic intraepithelial neoplasia (PIN), associated with increased prostate epithelial cell proliferation, epithelial mesenchymal transition (EMT), DNA damage and inflammation. Conclusions: DACH1 gene deletion may define a distinct subclass of prostate cancer that may benefit from PARP inhibitors, and platinum-based chemotherapy. Citation Format: Xuanmao Jiao, Gabriele Di Sante, Zhiping Li, Agnese Di Rocco, Min Wang, Adam Ertel, Peter A. McCue, Andrew P. South, Carlos Cordon-Cardo, Matthew P. Stokes, Marco Marra, Steven J. Jones, Andrew Kossenkov, Richard G. Pestell. DACH1 gene deletion extends portraits of human prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1730.