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Grant Details

Grant Number: 5R03CA108369-02 Interpret this number
Primary Investigator: Zhu, Yong
Organization: Yale University
Project Title: Methylation Related Genes and Breast Cancer Risk
Fiscal Year: 2005
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Abstract

DESCRIPTION (provided by applicant): Cancer has been recently recognized as a manifestation of both abnormal genetic and epigenetic events. Dysregulated epigenetic changes usually represented by abnormal DNA methylation patterns, such as global hypomethylation and region-specific hypermethylation, are a hallmark of most cancers, including breast cancer. Although the precise mechanisms underlying alterations of methylation patterns are far from complete, the overall methylation process is mainly regulated by a group of regulatory proteins including DNA methyltransferases (DNMTs) and methyl-cytosine guanine dinucleotide (CpG) binding proteins (MBDs). In this proposal, we hypothesize that adverse genotypes associated with methylation related genes may modulate their protein functions in epigenetic regulation, thereby influencing individual's susceptibility to human breast cancer. Our specific aims are: 1) To identify single nucleotide polymorphisms (SNPs) with potential functional impact on methylation related 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 playin the modulation of breast cancer risk. Our hypothesis is that SNPs predicted to have functional significance in methylation process may be a panel of biomarkers to be associated with breast cancer risk. 3) To investigate the joint-effect between methylation related genes and environmental factors. Our hypothesis is that exposure to tobacco smoking, alcohol consumption and environmental estrogens may modify the risk of breast cancer for individuals with the putative high-risk genotypes in methylation related 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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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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