Genes Relevant to Tissue Response to Cancer Therapy Display Diurnal Variation in mRNA Expression in Human Oral Mucosa.

Abstract

Background: To address a critical gap for application of cancer chronotherapy of when would be the best time(s) for treating an individual cancer patient, we conducted a pilot study to characterize diurnal variations of gene expression in oral mucosal tissue, which is vulnerable to damage from cancer therapies.

Methods: We conducted RNA-seq assay on individual oral mucosal samples collected from 11 healthy volunteers every 4 hours (6 time points). Using a cosine-based method, we estimated the individual and average values of peak-time and amplitude for each gene. Correlations between gene expression peak-times and age was examined, adjusting for individual's sleep timing.

Results: Among candidate gene pathways that are relevant to treatment response, 7 of 16 genes (PER3, CIART, TEF, PER1, PER2, CRY2, ARNTL) involved in circadian regulation and 1 of 118 genes (WEE1) involved in cell cycle regulation achieved p-value ≤ 0.1 and relative amplitude>0.1. The average peak times were approximately 10:15 for PER3, CIART and TEF, 10:45 for PER1, 13:00 for WEE1, PER2 and CRY2, and 19:30 for ARNTL. Ranges in peak times across individuals differed by gene (e.g., 8 hours for PER1; 16.7 hours for WEE1). Older people had later peak times for PER1 (r = 0.77, p = 0.03) and PER3 (r = 0.69, p-value = 0.06).

Conclusion: In oral mucosa, expression of some genes relevant to treatment response displayed diurnal variation. These genes may be candidates for development of biomarkers for optimizing individual timing of cancer therapy using non-invasively collected oral mucosa.