Abstract 2598: The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, augments DNA damage repair and predicts therapy responses

Abstract

Background: Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Methods: Analysis of DACH1 gene deletion and gene expression was conducted from public data bases and human prostate cancer samples. Transgenic mice were generated in which the Dach1 gene was deleted in the prostate of prostate Oncomice. Cells derived from Dach1 gene deletion mice and human prostate cancer cell lines with Dach1 knockdown were analyzed for DNA damage repair responses. Results: DACH1 gene deletion within the 13q21.31-q21.33 region, occurred in up to 18% of human PCa, and was associated with increased AR activity, and poor prognosis. DACH1 homozygous deletions more frequent in the metastatic site than in the primary tumors (Mich: 10% vs. 18%, N=59; FHCRC: 4% vs.11%, N= 54, SU2C: not profiled vs. 3.3, N=150). The prevalence of DACH1 heterozygous deletions was higher in the metastatic lesions than in primary tumors within a given cohort for three of six cohorts (Mich: 27.3% vs. 36%, N=59; FHCRC: 15% vs. 59%, N=54; SU2C: 0% vs. 26%, N=150, respectively). The patients with homozygous DACH1 deletions had reduced overall survival (medians of 84 vs. 120 months, N=667, log rank test P=9.3x10-3). Low DACH1 gene expression (expressed as a z-score with a z-score threshold of -1.25) was significantly correlated with earlier biochemical recurrence (BCR, log rank p value = 4.7x10-4, n=79). In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN) and was associated with increased DNA damage. Reduced Dach1 increased DNA damage in responses to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with resistance to TGFβ kinase and PARP inhibitors. Conclusions: Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies. Citation Format: Zhiping Li, Xuanmao Jiao, Gordon Robertson, Gabriele Di Sante, Anthony W. Ashton, Agnese DiRocco, Min Wang, Jun Zhao, Sankar Addya, Chenguang Wang, Peter A. McCue, Andrew P. South, Carlos Cordon-Cardo, Runzhi Liu, Kishan Patel, Rasha Hamid, Jorim Parmar, James B. DuHadaway, Nikolaus Schultz, Andrew Kossenkov, Lai Yee Phoon, Hao Chen, Li Lan, Yunguang Sun, Kenneth A. Iczkowski, Hallgeir Rui, Richard G. Pestell. The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, augments DNA damage repair and predicts therapy responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2598.