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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

Phenotypic effects of the circadian gene Cryptochrome 2 on cancer-related pathways.
Authors: Hoffman AE, Zheng T, Ba Y, Stevens RG, Yi CH, Leaderer D, Zhu Y
Source: BMC Cancer, 2010 Mar 24;10, p. 110.
EPub date: 2010 Mar 24.
PMID: 20334671
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The core circadian gene Cryptochrome 2 influences breast cancer risk, possibly by mediating hormone signaling.
Authors: Hoffman AE, Zheng T, Yi CH, Stevens RG, Ba Y, Zhang Y, Leaderer D, Holford T, Hansen J, Zhu Y
Source: Cancer Prev Res (Phila), 2010 Apr;3(4), p. 539-48.
EPub date: 2010 Mar 16.
PMID: 20233903
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CLOCK in breast tumorigenesis: genetic, epigenetic, and transcriptional profiling analyses.
Authors: Hoffman AE, Yi CH, Zheng T, Stevens RG, Leaderer D, Zhang Y, Holford TR, Hansen J, Paulson J, Zhu Y
Source: Cancer Res, 2010 Feb 15;70(4), p. 1459-68.
EPub date: 2010 Feb 2.
PMID: 20124474
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Testing the circadian gene hypothesis in prostate cancer: a population-based case-control study.
Authors: Zhu Y, Stevens RG, Hoffman AE, Fitzgerald LM, Kwon EM, Ostrander EA, Davis S, Zheng T, Stanford JL
Source: Cancer Res, 2009 Dec 15;69(24), p. 9315-22.
PMID: 19934327
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The circadian gene NPAS2 is a novel prognostic biomarker for breast cancer.
Authors: Yi C, Mu L, de la Longrais IA, Sochirca O, Arisio R, Yu H, Hoffman AE, Zhu Y, Katsaro D
Source: Breast Cancer Res Treat, 2010 Apr;120(3), p. 663-9.
EPub date: 2009 Aug 1.
PMID: 19649706
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microRNA miR-196a-2 and breast cancer: a genetic and epigenetic association study and functional analysis.
Authors: Hoffman AE, Zheng T, Yi C, Leaderer D, Weidhaas J, Slack F, Zhang Y, Paranjape T, Zhu Y
Source: Cancer Res, 2009 Jul 15;69(14), p. 5970-7.
EPub date: 2009 Jun 30.
PMID: 19567675
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Cancer-related transcriptional targets of the circadian gene NPAS2 identified by genome-wide ChIP-on-chip analysis.
Authors: Yi CH, Zheng T, Leaderer D, Hoffman A, Zhu Y
Source: Cancer Lett, 2009 Nov 1;284(2), p. 149-56.
EPub date: 2009 May 19.
PMID: 19457610
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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 AE, Zheng T, Stevens RG, Ba Y, Zhang Y, Leaderer D, Yi C, Holford TR, Zhu Y
Source: Cancer Res, 2009 Apr 15;69(8), p. 3605-13.
EPub date: 2009 Mar 24.
PMID: 19318546
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The circadian gene NPAS2, a putative tumor suppressor, is involved in DNA damage response.
Authors: Hoffman AE, Zheng T, Ba Y, Zhu Y
Source: Mol Cancer Res, 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: Mutat Res, 2008 Mar 1;639(1-2), p. 80-8.
EPub date: 2007 Nov 26.
PMID: 18191955
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Clock-cancer connection in non-Hodgkin's lymphoma.
Authors: Zhu Y, Zheng T
Source: Med Hypotheses, 2008;70(4), p. 788-92.
EPub date: 2007 Nov 1.
PMID: 17935900
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Non-synonymous polymorphisms in the circadian gene NPAS2 and breast cancer risk.
Authors: Zhu Y, Stevens RG, Leaderer D, Hoffman A, Holford T, Zhang Y, Brown HN, Zheng T
Source: Breast Cancer Res Treat, 2008 Feb;107(3), p. 421-5.
EPub date: 2007 Apr 24.
PMID: 17453337
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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 HN, Zhang Y, Boyle P, Stevens RG, Hoffman A, Qin Q, Han X, Zheng T
Source: Int J Cancer, 2007 Jan 15;120(2), p. 432-5.
PMID: 17096334
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Does "clock" matter in prostate cancer?
Authors: Zhu Y, Zheng T, Stevens RG, Zhang Y, Boyle P
Source: Cancer Epidemiol Biomarkers Prev, 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 HN, Zhang Y, Holford TR, Zheng T
Source: Breast Cancer Res, 2005;7(5), p. R745-52.
EPub date: 2005 Jul 19.
PMID: 16168120
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Period3 structural variation: a circadian biomarker associated with breast cancer in young women.
Authors: Zhu Y, Brown HN, Zhang Y, Stevens RG, Zheng T
Source: Cancer Epidemiol Biomarkers Prev, 2005 Jan;14(1), p. 268-70.
PMID: 15668506
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