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.
Highlights
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
Circadian rhythms in mitotic index and DNA synthesis, the major events in the M and S phase of a cell cycle, have been documented in epithelium of mouse alimentary tract [18, 19], as well as in human rectal and oral mucosa [20, 21]; these findings provide a foundation for using markers of cell cycle progression as potential biomarkers for development of personalized chronotherapeutic schedules for cancer treatment
Using gene expression data of all 66 samples from 11 participants, we examined the correlation between mRNA expression of circadian genes and WEE1, a gene involved in G2/M cell cycle checkpoint inhibition, using repeated measures correlation method accounting for intra-participant variation as implemented in R package rmcorr (v0.3.0) [39]
Summary
Conducting cancer therapy at optimal times of day based on circadian variations of sensitivity to cancer treatment (chronotherapy) has great potential for improving therapeutic efficacy and/or decreasing side effects [1, 2]. We and others have shown that the severity of OM may depend on time of radiotherapy [2, 6, 7]: patients treated in the morning have less severe OM These findings are biologically plausible, as many key regulators of fundamental biological processes that influence tissue response to cancer therapy, such as cell cycle progression [8,9,10,11] and DNA damage response [12], are under circadian control [13].
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