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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
1R03CA108369-01
Application #
6795177
Study Section
Special Emphasis Panel (ZCA1-SRRB-Q (J1))
Program Officer
Mikhail, Isis S
Project Start
2004-03-01
Project End
2006-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$81,750
Indirect Cost
Name
Yale University
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Zhu, Yong; Zheng, Tongzhang; Stevens, Richard G et al. (2006) Does ""clock"" matter in prostate cancer? Cancer Epidemiol Biomarkers Prev 15:3-5

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