Introduction: In experimental and epidemiological studies, alterations in several core circadian genes at the germline and tumor level have been associated with prostate cancer. The aim of this study was to investigate mRNA expression of circadian related genes in men with metastatic castration-resistant prostate cancer (mCRPC), and the association with survival.

Methods: We assessed whole exome and RNA sequencing data from 317 mCRPC patients from the Stand Up to Cancer-Prostate Cancer Foundation (SU2C-PCF) database. Data were obtained from six sites: metastasis to bone (n=107; n=65 deaths), lymph node (n=129; n=88 deaths), liver (n=42; n=35 deaths), lung (n=6; n=3 deaths), and other soft tissue (n=26; n=20 deaths), as well as primary prostate (n=7; n=5 deaths) over a median follow-up of 71.8 months. We evaluated expression of twelve core circadian genes (ARNTL, CLOCK, CRY1, CRY2, CSNK1E, NR1D1, NPAS2, PER1, PER2, PER3, RORA, TIMELESS) as transcripts per million (TPM). We used the correlation of correlations method to estimate inter-gene correlations between tissue. Unpaired Wilcoxon rank sum tests compared circadian expression differences with tumor mutations in AR and p53, two of the most common genomic alterations in mCRPC. We conducted multivariable Cox regression, overall and stratified by tissue type, to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for expression (modeled continuously) and overall survival, adjusted for age and PSA at diagnosis, Gleason, treatment, and histology.

Results: Many genes showed low or negative correlation across tissues, with the greatest discordance in CSNK1E (μICC=0.10), and greatest concordance in TIMELESS (μICC=0.55). Lower expression of ARNTL was found in patients with alterations to both p53 and AR. Similarly, higher expression of PER2 and RORA was found in AR-/p53+, compared to those AR+ and AR-/p53-. Higher expression of TIMELESS was associated with risk of death overall and across all tissue sites (HRoverall: 1.02, 95% CI: 1.01-1.03). In liver, higher expression of CLOCK (HR: 0.22, 95% CI: 0.07 - 0.71) and CSNK1E (HR: 0.87, 95% CI: 0.76 - 1.00), and lower expression of CRY1 (HR: 1.62, 95% CI: 1.16 - 2.26) was associated with a lower risk of death. Higher expression of CRY2 (HR: 1.25, 95% CI: 1.02 - 1.53) in liver, but lower expression in bone (HR: 0.95, 95% CI: 0.90 - 1.00) was associated with an increased risk of death. We found no association between ARNTL, NR1D1, NPAS2, PER3, or RORA and survival in any metastatic site.

Conclusion: Our results show that circadian gene expression is altered in tissue from mCRPC patients, with substantial heterogeneity in circadian related expression patterns between metastatic tissue sites. These results support prior research on the role of circadian gene expression, particularly CRY1 and CLOCK, and outcomes in localized prostate cancer.

Citation Format: Benjamin D. Booker, Konrad H. Stopsack, Travis A. Gerke, Kathryn Penny, Philip W. Kantoff, Lorelei A. Mucci, Sarah C. Markt, PCF/SU2C International Prostate Cancer Dream Team. Circadian gene expression in metastatic sites and association with survival in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 863.