Abstract 1574: Circadian clock gene expression and lethal prostate cancer outcomes
Authors: Markt Sarah C. , Ebot Ericka , Cheng Iona , Wilkens Lynne , Shafi Ayesha , Knudsen Karen , Penney Kathryn , Mucci Lorelei , Gerke Travis 
Published: August 2019

Background: Converging evidence points to a potential role of disruption of the circadian rhythm in prostate cancer progression. There is limited human data in prostate tissue examining the biological consequences of alterations in genes involved in circadian rhythm on outcomes among prostate cancer patients.

Methods: To test the hypothesis that tissue expression of circadian-related genes was associated with prostate cancer outcomes, we leveraged data from the Physicians' Health Study (PHS) and the Health Professionals Follow-Up Study (HPFS) prostate tumor cohorts. Whole transcriptome expression profiling was performed on 404 prostate cancer cases, including 113 lethal cases (metastatic disease or prostate cancer death) and 291 indolent cases (&gt;8 years from diagnosis without evidence of metastasis). Using logistic regression models, we assessed whether mRNA expression levels in tumor (N=404) or paired normal prostate tissue (N=202) of eleven circadian-related genes (AANAT, CLOCK, CRY1, CRY2, CSNK1E, MTNR1B, NPAS2, OPN4, PER1, PER2, PER3) were associated with lethal prostate cancer, stage (T2 vs. T3+), Gleason grade at diagnosis (&lt;8 vs. ≥8), and biomarkers of angiogenesis and apoptosis. We calculated odds ratios and 95% confidence intervals (95% CIs) per standard deviation increase in gene expression.

Results: Pathway analyses showed a statistically significant association between the eleven circadian genes and lethal disease (global test p-value = 5.1e-05). On an individual gene level, men with higher tumor expression of Period Circadian Regulator 1 (PER1) gene had a reduced risk of lethal disease, independent of grade and stage (OR: 0.75, 95% CI: 0.59-0.97). High tumor expression of PER1 (OR: 0.72, 95% CI: 0.57-0.91) and Cryptochrome Circadian Regulator 2 (CRY2) (OR: 0.79, 95% CI: 0.63-1.00) were associated with lower Gleason grade tumors. High tumor expression of PER1 was associated with lower levels of cell proliferation and lower levels of angiogenesis markers; Neuronal PAS Domain Protein 2 (NPAS2) was associated with markers of apoptosis. For none of the genes was expression in normal prostate tissue associated with lethal prostate cancer (global test p-value = 0.06).

Discussion: We found higher expression of several of the circadian related genes were associated with less aggressive prostate cancer features. In line with these findings, PER1 has been suggested to be a tumor suppressor in previous studies. This supports the idea that maintenance of circadian clock function may protect tumor progression.

Citation Format: Sarah C. Markt, Ericka Ebot, Iona Cheng, Lynne Wilkens, Ayesha Shafi, Karen Knudsen, Kathryn Penney, Lorelei Mucci, Travis Gerke. Circadian clock gene expression and lethal prostate cancer outcomes [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 1574.