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. 2025 Sep 3;3(1):60.
doi: 10.1038/s44276-025-00176-9.

Blood Clock Correlation Distance (BloodCCD) as a novel marker to detect circadian rhythm disruption in cancer survivors with insomnia

Brian J Altman  1   2 , Po-Ju Lin  3   4 , Lindsey J Mattick  4 , Elliot H Outland  5 , Javier Bautista  4 , Chin-Shang Li  4 , Umang Gada  4 , Kristina M Morris  6 , Amelia M Knudsen-Clark  7 , Daniel Mwangi  6 , Rachel E DeRollo  6 , Amber S Kleckner  8 , Ian R Kleckner  8 , Nikesha J Gilmore  3   4 , Benjamin T Esparaz  9 , Amarinthia Curtis  10 , Alison Conlin  11 , Gianni Monaco  12 , Jacob J Hughey  5 , Karen M Mustian  3   4
Affiliations

Blood Clock Correlation Distance (BloodCCD) as a novel marker to detect circadian rhythm disruption in cancer survivors with insomnia

Brian J Altman et al. BJC Rep. .

Abstract

Background: Insomnia is a toxicity of cancer and treatment for survivors without an objective biochemical measure. Circadian rhythms are 24-h cycles that influence physiologic processes including sleep, and disrupted rhythms may contribute to insomnia. Here, we use BloodCCD to assess circadian rhythms from RNA-sequencing of blood from cancer survivors with insomnia from the YOCAS-II trial. YOCAS-II aimed to determine whether YOCAS©® yoga or cognitive behavioral therapy for insomnia (CBT-I) improved insomnia in survivors compared with a behavioral placebo. We hypothesized that circadian rhythms are disrupted in survivors, and that insomnia severity correlates with the degree of circadian disruption.

Methods: BloodCCD was developed to biochemically assess circadian rhythms in blood. It was adapted from the previously published Clock Correlation Distance (CCD) and uses a correlation matrix of 42 genes known to oscillate throughout the day in blood.

Results: Cancer survivors had higher (worse) BloodCCD scores, indicating disrupted circadian clock, compared to healthy individuals. Furthermore, insomnia severity correlated with worse BloodCCD, and those in the YOCAS and behavioral placebo arm showed significant correlation between BloodCCD score and insomnia.

Conclusions: BloodCCD shows promise as a biomarker to biochemically detect disrupted circadian rhythms in cancer survivors, and as an indicator for insomnia severity.

Clinical trial identifier: NCT02613364.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: The YOCAS-II trial (NCT02613364) including the consent form, all original study procedures, and all procedures associated with this study and use of biological samples, was approved by a central Institutional Review Board (IRB) at the University of Rochester and all IRBs at collaborating sites. All participants provided informed consent which included agreement to provide biological samples to be banked and used for future research. The YOCAS-II trial was approved by the Research Subjects Review Board (RSRB) is the University’s IRB, STUDY00000554, and the BloodCCD research was deemed exempt and approved by the RSRB, STUDY00005516. This study was performed in accordance with the Declaration of Helsinki. Consent for publication: This manuscript contains no personally identifiable information (PII) or protected health information (PHI).

Figures

Fig. 1
Fig. 1. Determination of oscillating genes from blood in healthy individuals.
Sequencing data from three publicly available studies (GSE39445, GSE48113, and GSE56931) were analyzed with ZeitZeiger and the elastic net (GLMNet) to identify oscillating genes in blood. Seven example oscillating genes and how their expression varies over time in each of the 3 studies are shown in the lower panel.
Fig. 2
Fig. 2. The 42 BloodCCD genes peak throughout the day.
a The 42-gene reference correlation for BloodCCD, presented as a heatmap of individual Spearman correlations between each gene. b Peak phase for the 42 genes selected by elastic net, calculated using limorhyde2 [103].
Fig. 3
Fig. 3. Comparison of BloodCCD in survivors and healthy individuals.
BloodCCD was compared between cancer-free healthy individuals from (from GSE56931) and the entire YOCAS-II cohort using a “leave-one-out” reference BloodCCD correlation that was built only from the GSE39445 and GSE48113 studies. P value (vs. cancer-free) is the delta BloodCCD comparison between these two groups.
Fig. 4
Fig. 4. BloodCCD and insomnia severity show a positive correlation.
Samples from the YOCAS-II trial were divided into 18 groups based on insomnia severity (subthreshold, moderate, severe), study arm, and timepoint (assessment 1 or 3), and BloodCCD was performed on each group (see Supplemental Table 2 for all values). a Least-square means comparison of BloodCCD scores only between the groups by study arm. P value is corrected for multiple testing with Tukey adjustment. b Linear regression of BloodCCD scores and ISI scores was performed. c Linear regression of BloodCCD scores and ISI scores by each individual study arm were performed. For b, c, regression statistics and 95% confidence intervals shown.
See this image and copyright information in PMC

References

    1. Schultz PN, Klein MJ, Beck ML, Stava C, Sellin RV. Breast cancer: relationship between menopausal symptoms, physiologic health effects of cancer treatment and physical constraints on quality of life in long-term survivors. J Clin Nurs. 2005;14:204–11. - PubMed
    1. Palesh OG, Roscoe JA, Mustian KM, Roth T, Savard J, Ancoli-Israel S, et al. Prevalence, demographics, and psychological associations of sleep disruption in patients with cancer: University of Rochester Cancer Center-Community Clinical Oncology Program. J Clin Oncol. 2010;28:292–8. - PMC - PubMed
    1. Ancoli-Israel S. Recognition and treatment of sleep disturbances in cancer. J Clin Oncol. 2009;27:5864–6. - PubMed
    1. Savard J, Ivers H, Villa J, Caplette-Gingras A, Morin CM. Natural course of insomnia comorbid with cancer: an 18-month longitudinal study. J Clin Oncol. 2011;29:3580–6. - PubMed
    1. Partinen M. Epidemiology of sleep disorders. Handb Clin Neurol. 2011;98:275–314. - PubMed

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