Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk

Authors

  • Alan Fu,

    1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
    Search for more papers by this author
  • Derek Leaderer,

    1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
    Search for more papers by this author
  • Tongzhang Zheng,

    1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
    Search for more papers by this author
  • Aaron E. Hoffman,

    1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
    Current affiliation:
    1. Department of Epidemiology, Tulane School of Public Health and Tropical Medicine and Tulane Cancer Center, New Orleans, LA.
    Search for more papers by this author
  • Richard G. Stevens,

    1. Department of Community Medicine and Health Care, University of Connecticut Health Center, Farmington, Connecticut
    Search for more papers by this author
  • Yong Zhu

    Corresponding author
    1. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
    • Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT 06520.
    Search for more papers by this author

  • The authors declare no conflicts of interest.

Abstract

Results from recent molecular epidemiologic studies suggest that the core circadian genes play a role in breast tumorigenesis, possibly by influencing hormone regulation or other pathways relevant to cancer. In order to further evaluate this hypothesis, we conducted a genetic and epigenetic association study of the circadian regulator TIMELESS in breast carcinogenesis. We detected significant associations between two tagging SNPs (rs2291738 and rs7302060) in the TIMELESS gene and breast cancer among 441 breast cancer cases and 479 cancer-free controls, with apparent effect modification by ER/PR status. The presence of the C allele of rs7302060 was found to be associated with reduced breast cancer risk (OR, 0.54; 95% CI, 0.54–0.99). In addition, both the G/G genotype of rs2291738 and the C/C genotype of rs7302060 were associated with reduced risk of breast cancer among ER- or PR-positive breast cancer cases (OR, 0.46; 95% CI, 0.22–0.97 and OR, 0.36; 95% CI, 0.17–0.78, respectively). We also observed a significant association between stage II, III, and IV breast cancers and TIMELESS promoter hypomethylation in peripheral blood lymphocytes (OR, 0.35; 95% CI, 0.13–0.96) in 80 breast cancer cases and 80 age-matched controls, which is corroborated by documented overexpression of TIMELESS in breast tumor tissue compared to adjacent normal tissue. Our findings support the hypothesized role of circadian genes in breast tumorigenesis, and identify a set of circadian biomarkers for breast cancer susceptibility. © 2011 Wiley Periodicals, Inc.

Ancillary