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Circadian clock genes and risk of fatal prostate cancer

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Abstract

Purpose

Circadian genes may be involved in regulating cancer-related pathways, including cell proliferation, DNA damage response, and apoptosis. We aimed to assess the role of genetic variation in core circadian rhythm genes with the risk of fatal prostate cancer and first morning void urinary 6-sulfatoxymelatonin levels.

Methods

We used unconditional logistic regression to evaluate the association of 96 single-nucleotide polymorphisms (SNPs) across 12 circadian-related genes with fatal prostate cancer in the AGES-Reykjavik cohort (n = 24 cases), the Health Professionals Follow-Up Study (HPFS) (n = 40 cases), and the Physicians’ Health Study (PHS) (n = 105 cases). We used linear regression to evaluate the association between SNPs and first morning void urinary 6-sulfatoxymelatonin levels in AGES-Reykjavik. We used a kernel machine test to evaluate whether multimarker SNP sets in the pathway (gene based) were associated with our outcomes.

Results

None of the individual SNPs were consistently associated with fatal prostate cancer across the three cohorts. In each cohort, gene-based analyses showed that variation in the CRY1 gene was nominally associated with fatal prostate cancer (p values = 0.01, 0.01, and 0.05 for AGES-Reykjavik, HPFS, and PHS, respectively). In AGES-Reykjavik, SNPs in TIMELESS (four SNPs), NPAS2 (six SNPs), PER3 (two SNPs) and CSNK1E (one SNP) were nominally associated with 6-sulfatoxymelatonin levels.

Conclusion

We did not find a strong and consistent association between variation in core circadian clock genes and fatal prostate cancer risk, but observed nominally significant gene-based associations with fatal prostate cancer and 6-sulfatoxymelatonin levels.

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Acknowledgments

We thank the study participants and the Icelandic Heart Association clinic staff for their invaluable contribution. We are grateful to the ongoing participation of men in the Health Professionals Follow-up Study (UM1 CA167552) and would like to acknowledge our colleagues (Lauren McLaughlin and Siobhan Saint-Surin) working on these studies for their valuable help. In addition, we would like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The AGES-Reykjavik is supported by Contract N01-AG-12100 from the National Institutes on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); and the Althingi (the Icelandic Parliament). In addition, this study was supported by funding from the Harvard Catalyst Award, the Icelandic Cancer Society, the National Cancer Institute at the National Institutes of Health (P01 CA055075, CA133891, CA42182, CA34944, CA40360, CA141298, CA98233 and CA097193); the National Heart, Lung, and Blood Institute at the National Institutes of Health (HL26490, HL34595). National Cancer Institute at the National Institutes of Health Training Grant (R25 CA098566 and T32 CA09001-35 to SCM); and the Prostate Cancer Foundation (to LAM and JRR); US Army Department of Defense Prostate Cancer Research Program Fellowship (to IMS). CAC was supported in part by NIH NIA Grant P01-AG-009975.

Conflict of interest

Dr. Czeisler has received consulting fees from or served as a paid member of scientific advisory boards for: Bombardier Inc., Boston Red Sox, Boston Celtics, Cephalon, Inc. (acquired by Teva Pharmaceutical Industries Ltd. October 2011), Michael Jackson’s mother and children, Koninklijke Philips Electronics, N.V., Novartis, United Parcel Service (UPS), Vanda Pharmaceuticals, Inc., and Zeo, Inc; owns an equity interest in Lifetrac, Inc., Somnus Therapeutics, Inc. and Vanda Pharmaceuticals, Inc.; received royalties from McGraw Hill, Penguin Press/Houghton Mifflin Harcourt, and Philips Respironics, Inc.; and has received research support from Cephalon, National Football League Charities, ResMed, and Philips Respironics. Dr. Czeisler is the incumbent of an endowed professorship provided to Harvard University by Cephalon, Inc., holds a number of process patents in the field of sleep/circadian rhythms (e.g., photic resetting of the human circadian pacemaker), and since 1985, has also served as an expert witness on various legal matters related to sleep and/or circadian rhythms.

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Authors and Affiliations

  1. Department of Epidemiology, Harvard School of Public Health, 677 Huntington Avenue, Boston, MA, 02115-6018, USA

    Sarah C. Markt, Unnur A. Valdimarsdottir, Irene M. Shui, Jennifer R. Rider, Rulla M. Tamimi, Julie L. Batista, Meir J. Stampfer, Sara Lindstrom, Peter Kraft & Lorelei A. Mucci

  2. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    Unnur A. Valdimarsdottir, Lara G. Sigurdardottir, Albert Vernon Smith & Vilmundur Gudnason

  3. Centre of Public Health Sciences, University of Iceland, Reykjavík, Iceland

    Unnur A. Valdimarsdottir, Lara G. Sigurdardottir & Lorelei A. Mucci

  4. The Icelandic Cancer Society, Reykjavík, Iceland

    Lara G. Sigurdardottir

  5. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    Jennifer R. Rider, Rulla M. Tamimi, Julie L. Batista, Meir J. Stampfer & Lorelei A. Mucci

  6. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA

    Sebastien Haneuse & Peter Kraft

  7. Division of Sleep Medicine, Harvard Medical School, Boston, MA, USA

    Erin Flynn-Evans, Steven W. Lockley & Charles A. Czeisler

  8. Division of Sleep Medicine, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Erin Flynn-Evans, Steven W. Lockley & Charles A. Czeisler

  9. Icelandic Heart Association, Kopavogur, Iceland

    Albert Vernon Smith & Vilmundur Gudnason

  10. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD, USA

    Lenore Launer & Tamara Harris

  11. Program in Molecular and Genetic Epidemiology, Harvard School of Public Health, Boston, MA, USA

    Sara Lindstrom & Peter Kraft

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  1. Sarah C. Markt
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  19. Lorelei A. Mucci
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Corresponding author

Correspondence to Sarah C. Markt.

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Markt, S.C., Valdimarsdottir, U.A., Shui, I.M. et al. Circadian clock genes and risk of fatal prostate cancer. Cancer Causes Control 26, 25–33 (2015). https://doi.org/10.1007/s10552-014-0478-z

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