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Grant Details

Grant Number: 5R01CA118447-03 Interpret this number
Primary Investigator: Han, Jiali
Organization: Brigham And Women'S Hospital
Project Title: Prospective Study of DNA Repair Gene Variants in Breast Cancer
Fiscal Year: 2009
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Abstract

DESCRIPTION (provided by applicant): Prospective Study of DNA Repair Gene Variants in Breast Cancer We propose to prospectively evaluate inherited polymorphisms in DNA repair and related genes with breast cancer risk in a large nested case-control study within the Nurses' Health Study (NHS) with 2096 pathologically confirmed incident breast cancer cases and 2979 matched controls. Specifically, we will comprehensively and systematically evaluate genetic variation in five DNA repair pathways, including base excision repair, nucleotide excision repair, double strand break repair (DNA damage response, homologous recombination and non-homologous end-joining), direct reversal repair, and mismatch repair, along with candidate DNA polymerases and Fanconi Anemia complementation groups. We will survey common genetic variation at each locus using two complementary approaches; 1) to evaluate nonsynonymous polymorphisms and 2) to choose tag-SNPs using high-density genotyping data to test for the association of common variants in regions of unknown functional relevance with breast cancer risk. We will evaluate a priori hypothesized interactions between the variants and folate status and antioxidant status (primarily a- and p- carotenes), as measured in pre-diagnostically collected plasma samples, on breast cancer risk. We will have substantial power to detect the main effects of most of the genotypes of interest and interactions between the genotypes and the biomarkers. Our study will add substantially to the body of evidence by evaluating in considerably more detail the roles of common variants in DNA repair genes in breast cancer etiology. Gene- environment interaction analysis involving genetic polymorphisms in DNA repair pathways may provide new insights into the genotoxic effects of exposures on breast cancer risk. Several unique features of the existing NHS cohort include cohort characteristics, quality of design, large sample size, rigor in prospective exposure assessment, high response and follow-up rates, and archived bio-specimens. This innovative work is essential to advance this field, and it has substantial potential for application to other areas of cancer susceptibility.

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Publications

Comprehensive screen of genetic variation in DNA repair pathway genes and postmenopausal breast cancer risk.
Authors: Monsees GM, Kraft P, Chanock SJ, Hunter DJ, Han J
Source: Breast Cancer Res Treat, 2011 Jan;125(1), p. 207-14.
EPub date: 2010 May 23.
PMID: 20496165
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Genetic variation in DNA repair pathway genes and premenopausal breast cancer risk.
Authors: Han J, Haiman C, Niu T, Guo Q, Cox DG, Willett WC, Hankinson SE, Hunter DJ
Source: Breast Cancer Res Treat, 2009 Jun;115(3), p. 613-22.
EPub date: 2008 Jun 13.
PMID: 18551366
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A prospective study of genetic polymorphism in MPO, antioxidant status, and breast cancer risk.
Authors: He C, Tamimi RM, Hankinson SE, Hunter DJ, Han J
Source: Breast Cancer Res Treat, 2009 Feb;113(3), p. 585-94.
EPub date: 2008 Mar 14.
PMID: 18340529
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Comprehensive association testing of common genetic variation in DNA repair pathway genes in relationship with breast cancer risk in multiple populations.
Authors: Haiman CA, Hsu C, de Bakker PI, Frasco M, Sheng X, Van Den Berg D, Casagrande JT, Kolonel LN, Le Marchand L, Hankinson SE, Han J, Dunning AM, Pooley KA, Freedman ML, Hunter DJ, Wu AH, Stram DO, Henderson BE
Source: Hum Mol Genet, 2008 Mar 15;17(6), p. 825-34.
EPub date: 2007 Dec 3.
PMID: 18056155
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Genetic association and functional studies of major polymorphic variants of MGMT.
Authors: Bugni JM, Han J, Tsai MS, Hunter DJ, Samson LD
Source: DNA Repair (Amst), 2007 Aug 1;6(8), p. 1116-26.
EPub date: 2007 Jun 13.
PMID: 17569599
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