Monitoring Chd1 During Prostate Cancer Progression

Adenocarcinomas of the prostate consist of a collection of malignancies with distinct molecular underpinnings. Linking molecular background to clinical behaviour, i.e. tumour progression and response to therapy has not yet been fully established. This is in large measure due to a paucity of well-annotated patient cohorts, which cover the evolution from localized, hormone naive to metastatic castration resistant prostate cancer. Deletions in the gene Chromodomain Helicase DNA Binding Protein 1 (CHD1) are among the most frequent genomic alterations in prostate cancer. CHD1 is a ATPase-dependent helicase mediating a variety of biological processes by modifying chromatin structure. In hormone sensitive prostate cancer, loss of CHD1 has been associated with increased genomic instability and aggressiveness. Here we monitor CHD1 status during the progression from hormone sensitive (HSPC) to castration resistant prostate cancer (CRPC). To molecularly stratify this patient subgroup we correlate CHD1 status with markers of prostate cancer including AR, ERG, PTEN and Ki67. Finally, we analyze the impact of alterations in CHD1 on outcome and response to therapy of CRPC patients. We retrospectively identified 52 patients of whom HSPC and CRPC tissue was available for immunohistochemical analysis of CHD1, ERG, PTEN, AR and Ki67 as well as for CHD1 fluorescence in situ hybridization. Relationship with outcome was analyzed using univariate Cox regression and log-rank analyses. By using Fluorescence In Situ Hybridization (FISH) and immunohistochemistry (IHC) in a cohort of 52 men who developed CRPC, we show that the frequency of loss of CHD1 does not change during disease progression (7.7% in HSPC vs 9.6% in CRPC). Homozygously deleted tumors demonstrate a tendency towards poorer prognosis but this observation lacks statistical power in our cohort. Interestingly, in patients that show CHD1 protein expression in their hormone naive sample, a decrease of expression in the matched CRPC sample correlates with poorer overall survival (OS) (p = 0.03). Although preclinical data suggest a role for CHD1 in androgen receptor (AR) activity, CHD1 expression did not correlate with AR protein level. Additionally, Ki67 expression did not show correlation with CHD1 levels of expression. Further molecular stratification confirms a known mutual exclusive relationship with the expression of the ERG transcription factor (p = 0.048). Clinically, although decreased CHD1 protein expression during disease progression correlated with worse outcome (overall survival (p = 0.03) and survival from diagnosis of CRPC (p = 0.02)), no significant impact on survival after docetaxel or abiraterone treatment was measured.Here we monitor CHD1 deletion during prostate cancer progression. Our results show that this genomic marker defines a distinct molecular subgroup of prostate cancer. In addition, loss of CHD1 protein expression during disease progression is associated with poorer clinical outcome. Citation Format: Gunther Boysen, Daniel Nava Rodrigues, Joaquin Mateo, Rossitza Christova, Ruth Riisnaes, Mateus Crespo, Theresa MacDonald, Susana Miranda, Ines Figueiredo, Veronica Gil, Sara Aziz, Adam Sharp, Niven Mehra, Pasquale Rescigno, Juan M. Mosquera, Christopher E. Barbieri, Mark A. Rubin, Johann S. de Bono. Monitoring CHD1 during prostate cancer progression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4976.