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Inherited variation in circadian rhythm genes and risks of prostate cancer and three other cancer sites in combined cancer consortia.
Pubmed ID
28699174 (View this publication on the PubMed website)
Digital Object Identifier
Int J Cancer. 2017 Nov 1; Volume 141 (Issue 9): Pages 1794-1802
Gu F, Zhang H, Hyland PL, Berndt S, Gapstur SM, Wheeler W, Ellipse Consortium T, Amos CI, Bezieau S, Bickeböller H, Brenner H, Brennan P, Chang-Claude J, Conti DV, Doherty JA, Gruber SB, Harrison TA, Hayes RB, Hoffmeister M, Houlston RS, more Hung RJ, Jenkins MA, Kraft P, Lawrenson K, McKay J, Markt S, Mucci L, Phelan CM, Qu C, Risch A, Rossing MA, Wichmann HE, Shi J, Schernhammer E, Yu K, Landi MT, Caporaso NE
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
  • Epidemiology Research Program, American Cancer Society, Atlanta, GA.
  • Information Management Services, Inc, Rockville, MD.
  • Geisel School of Medicine at Dartmouth, Lebanon, NH.
  • Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • Department of Genetic Epidemiology, University Medical Center Göttingen, Göttingen, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • International Agency for Research on Cancer, Lyon, France.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Keck School of Medicine, University of South California, Los Angeles, CA. more
  • Huntsman Cancer Institute, University of Utah, Salt Lake City, UT.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Department of Population Health, New York University School of Medicine, New York, NY.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey, United Kingdom.
  • Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Parkville, VIC, Australia.
  • Department of Epidemiology, Harvard T.H Chan School of Public Health, Boston, MA.
  • Cedars-Sinai Medical Center, Los Angeles, CA.
  • Department of Cancer Epidemiology, Population Sciences Division, Moffitt Cancer Center, Tampa, FL.
  • Division of Molecular Biology, University of Salzburg, Salzburg, Austria.
  • Institute of Medical Informatics, Biometry and Epidemiology, University of Munich, Munich, Bavaria, Germany.

Circadian disruption has been linked to carcinogenesis in animal models, but the evidence in humans is inconclusive. Genetic variation in circadian rhythm genes provides a tool to investigate such associations. We examined associations of genetic variation in nine core circadian rhythm genes and six melatonin pathway genes with risk of colorectal, lung, ovarian and prostate cancers using data from the Genetic Associations and Mechanisms in Oncology (GAME-ON) network. The major results for prostate cancer were replicated in the Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial, and for colorectal cancer in the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). The total number of cancer cases and controls was 15,838/18,159 for colorectal, 14,818/14,227 for prostate, 12,537/17,285 for lung and 4,369/9,123 for ovary. For each cancer site, we conducted gene-based and pathway-based analyses by applying the summary-based Adaptive Rank Truncated Product method (sARTP) on the summary association statistics for each SNP within the candidate gene regions. Aggregate genetic variation in circadian rhythm and melatonin pathways were significantly associated with the risk of prostate cancer in data combining GAME-ON and PLCO, after Bonferroni correction (ppathway  < 0.00625). The two most significant genes were NPAS2 (pgene  = 0.0062) and AANAT (pgene  = 0.00078); the latter being significant after Bonferroni correction. For colorectal cancer, we observed a suggestive association with the circadian rhythm pathway in GAME-ON (ppathway  = 0.021); this association was not confirmed in GECCO (ppathway  = 0.76) or the combined data (ppathway  = 0.17). No significant association was observed for ovarian and lung cancer. These findings support a potential role for circadian rhythm and melatonin pathways in prostate carcinogenesis. Further functional studies are needed to better understand the underlying biologic mechanisms.

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