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Grant Details

Grant Number: 5R03CA110937-02 Interpret this number
Primary Investigator: Zhu, Yong
Organization: Yale University
Project Title: Circadian Genes and Breast Cancer
Fiscal Year: 2005
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Abstract

DESCRIPTION (provided by applicant): Emerging data have demonstrated that circadian genes are involved in regulating cell proliferation and apoptosis by controlling expression of tumor suppressor genes, cell cycle genes, as well as genes that encode the caspases and transcription factors. Therefore, as the molecular clockworks regulate many biological pathways in tumorigenesis, mutations in circadian genes could conceivably result in deregulation of these processes and tumour development. In this proposal, we hypothesize that adverse genotypes associated with these circadian genes may modulate their protein functions in biology rhythms, thereby influencing an individual's susceptibility to human cancer. Our specific aims are: 1) To identify single nucleotide polymorphisms (SNPs) with potential functional impact on circadian genes. SNPs will be collected from public SNP databases and screened by different bioinformatic tools. Prediction about functional impact will be made to both SNPs that alter an amino acid and SNPs located in the exonic splicing sites. 2) To determine the role that specific polymorphisms in these genes play in the modulation of breast cancer risk. Our hypothesis is that SNPs predicted to have functional significance in circadian genes may be a novel panel of biomarkers to be associated with breast cancer risk. 3) To investigate the joint-effect between circadian genes and environmental factors, especially night exposure to light. Light is the most powerful circadian synchronizer among all environmental cues. Our hypothesis is that exposure to light at night may disturb circadian rhythms and consequently increase the risk of breast cancer for individuals with the putative high-risk genotypes in circadian genes. Given the availability of DNA samples and exposure data, this proposal is both time and cost effective in terms of practical feasibility.

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Publications

Genetic and epigenetic association studies suggest a role of microRNA biogenesis gene exportin-5 (XPO5) in breast tumorigenesis.
Authors: Leaderer D. , Hoffman A.E. , Zheng T. , Fu A. , Weidhaas J. , Paranjape T. , Zhu Y. .
Source: International journal of molecular epidemiology and genetics, 2011-01-01; 2(1), p. 9-18.
EPub date: 2010-11-25.
PMID: 21552306
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The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling.
Authors: Hoffman A.E. , Zheng T. , Yi C.H. , Stevens R.G. , Ba Y. , Zhang Y. , Leaderer D. , Holford T. , Hansen J. , Zhu Y. .
Source: Cancer prevention research (Philadelphia, Pa.), 2010 Apr; 3(4), p. 539-48.
EPub date: 2010-03-16.
PMID: 20233903
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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.
Authors: Yi C. , Mu L. , de la Longrais I.A. , Sochirca O. , Arisio R. , Yu H. , Hoffman A.E. , Zhu Y. , Katsaro D. .
Source: Breast cancer research and treatment, 2010 Apr; 120(3), p. 663-9.
EPub date: 2009-08-01.
PMID: 19649706
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Phenotypic effects of the circadian gene Cryptochrome 2 on cancer-related pathways.
Authors: Hoffman A.E. , Zheng T. , Ba Y. , Stevens R.G. , Yi C.H. , Leaderer D. , Zhu Y. .
Source: BMC cancer, 2010-03-24; 10, p. 110.
EPub date: 2010-03-24.
PMID: 20334671
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CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses.
Authors: Hoffman A.E. , Yi C.H. , Zheng T. , Stevens R.G. , Leaderer D. , Zhang Y. , Holford T.R. , Hansen J. , Paulson J. , Zhu Y. .
Source: Cancer research, 2010-02-15; 70(4), p. 1459-68.
EPub date: 2010-02-02.
PMID: 20124474
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Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study.
Authors: Zhu Y. , Stevens R.G. , Hoffman A.E. , Fitzgerald L.M. , Kwon E.M. , Ostrander E.A. , Davis S. , Zheng T. , Stanford J.L. .
Source: Cancer research, 2009-12-15; 69(24), p. 9315-22.
PMID: 19934327
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Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis.
Authors: Yi C.H. , Zheng T. , Leaderer D. , Hoffman A. , Zhu Y. .
Source: Cancer letters, 2009-11-01; 284(2), p. 149-56.
EPub date: 2009-05-19.
PMID: 19457610
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microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.
Authors: Hoffman A.E. , Zheng T. , Yi C. , Leaderer D. , Weidhaas J. , Slack F. , Zhang Y. , Paranjape T. , Zhu Y. .
Source: Cancer research, 2009-07-15; 69(14), p. 5970-7.
EPub date: 2009-06-30.
PMID: 19567675
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Clock-cancer connection in non-Hodgkin's lymphoma: a genetic association study and pathway analysis of the circadian gene cryptochrome 2.
Authors: Hoffman A.E. , Zheng T. , Stevens R.G. , Ba Y. , Zhang Y. , Leaderer D. , Yi C. , Holford T.R. , Zhu Y. .
Source: Cancer research, 2009-04-15; 69(8), p. 3605-13.
EPub date: 2009-03-24.
PMID: 19318546
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The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.
Authors: Hoffman A.E. , Zheng T. , Ba Y. , Zhu Y. .
Source: Molecular cancer research : MCR, 2008 Sep; 6(9), p. 1461-8.
PMID: 18819933
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Correlating observed odds ratios from lung cancer case-control studies to SNP functional scores predicted by bioinformatic tools.
Authors: Zhu Y. , Hoffman A. , Wu X. , Zhang H. , Zhang Y. , Leaderer D. , Zheng T. .
Source: Mutation research, 2008-03-01; 639(1-2), p. 80-8.
EPub date: 2007-11-26.
PMID: 18191955
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Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk.
Authors: Zhu Y. , Stevens R.G. , Leaderer D. , Hoffman A. , Holford T. , Zhang Y. , Brown H.N. , Zheng T. .
Source: Breast cancer research and treatment, 2008 Feb; 107(3), p. 421-5.
EPub date: 2007-04-24.
PMID: 17453337
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Clock-cancer connection in non-Hodgkin's lymphoma.
Authors: Zhu Y. , Zheng T. .
Source: Medical hypotheses, 2008; 70(4), p. 788-92.
EPub date: 2007-11-01.
PMID: 17935900
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Ala394Thr polymorphism in the clock gene NPAS2: a circadian modifier for the risk of non-Hodgkin's lymphoma.
Authors: Zhu Y. , Leaderer D. , Guss C. , Brown H.N. , Zhang Y. , Boyle P. , Stevens R.G. , Hoffman A. , Qin Q. , Han X. , et al. .
Source: International journal of cancer, 2007-01-15; 120(2), p. 432-5.
PMID: 17096334
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Does "clock" matter in prostate cancer?
Authors: Zhu Y. , Zheng T. , Stevens R.G. , Zhang Y. , Boyle P. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2006 Jan; 15(1), p. 3-5.
PMID: 16434577
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Genotypes and haplotypes of the methyl-CpG-binding domain 2 modify breast cancer risk dependent upon menopausal status.
Authors: Zhu Y. , Brown H.N. , Zhang Y. , Holford T.R. , Zheng T. .
Source: Breast cancer research : BCR, 2005; 7(5), p. R745-52.
EPub date: 2005-07-19.
PMID: 16168120
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Period3 structural variation: a circadian biomarker associated with breast cancer in young women.
Authors: Zhu Y. , Brown H.N. , Zhang Y. , Stevens R.G. , Zheng T. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2005 Jan; 14(1), p. 268-70.
PMID: 15668506
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