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Grant Details

Grant Number: 5R01CA064277-12 Interpret this number
Primary Investigator: Zheng, Wei
Organization: Vanderbilt University
Project Title: Shanghai Breast Cancer Study
Fiscal Year: 2010
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Abstract

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy among women in the United States and many other parts of the world. It is believed that most breast cancers are caused by genetic factors and gene-environment interactions. Over the past 10 years many genetic polymorphisms have been investigated in relation to breast cancer risk, yet few of the associations found have been confirmed. As part of this renewal application for the Shanghai Breast Cancer Study (SBCS R01CA64277), a large population-based case-control study of breast cancer funded by NCI since 1996, we propose several novel approaches to circumvent the limitations of the methodologies currently used for studying low-penetrance genetic variants for the risk of complex, multifactorial diseases. First, in addition to studying common genetic variants using haplotype tagging SNPs (htSNP), we propose to test the hypothesis that a large part of breast cancer susceptibility may be due to the summation of the effect from multiple low-frequency genetic variants. We also propose to use resequencing data to enhance htSNP selection and reduce misclassification errors and use quantitative functional data to define risk groups. With these new approaches, we will comprehensively evaluate genetic polymorphisms in the TGF2 signaling pathway in a two-phase study including approximately 6200 cases and controls. Genetic variants in major TGF2 pathway genes will be screened in Phase I, and promising associations will be validated in Phase II along with a series of in vitro functional assays. Breast cancer patients are being followed for cancer recurrence, relapse, and death, and the association of TGF2 pathway gene variants with breast cancer survival will be evaluated in a two-phase study. Numerous in vitro and animal studies have clearly demonstrated that the TGF2 signaling pathway plays a pivotal role in the development and progression of breast cancer. It remains unclear, however, whether these laboratory findings can be translated into cancer prevention strategies and clinical practice. The proposed study, with its strong methodology and novel approaches, has outstanding potential for discovering genetic markers that will be valuable in identifying high- risk women for cost-efficient breast cancer prevention and personalized treatment and follow-up care after cancer diagnosis. The proposed novel approaches will not only facilitate the evaluation of the study hypotheses, but also provide significant data to expand and guide future studies of low-penetrance genetic factors for breast cancer and other complex, multifactorial diseases. PUBLIC HEALTH RELEVANCE: It is believed that most breast cancers are caused by genetic factors and gene- environment interactions. Herein, we propose a large epidemiologic study to comprehensively evaluate genetic markers in relation to breast cancer risk and survival. The results from this study will be valuable in identifying high-risk women for cost- efficient breast cancer prevention and personalized treatment and follow-up care after cancer diagnosis.

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Publications

Genome-wide association study identifies a common variant associated with risk of endometrial cancer.
Authors: Spurdle AB, Thompson DJ, Ahmed S, Ferguson K, Healey CS, O'Mara T, Walker LC, Montgomery SB, Dermitzakis ET, Australian National Endometrial Cancer Study Group, Fahey P, Montgomery GW, Webb PM, Fasching PA, Beckmann MW, Ekici AB, Hein A, Lambrechts D, Coenegrachts L, Vergote I, Amant F, Salvesen HB, Trovik J, Njolstad TS, Helland H, Scott RJ, Ashton K, Proietto T, Otton G, National Study of Endometrial Cancer Genetics Group, Tomlinson I, Gorman M, Howarth K, Hodgson S, Garcia-Closas M, Wentzensen N, Yang H, Chanock S, Hall P, Czene K, Liu J, Li J, Shu XO, Zheng W, Long J, Xiang YB, Shah M, Morrison J, Michailidou K, Pharoah PD, Dunning AM, Easton DF
Source: Nat Genet, 2011 May;43(5), p. 451-4.
EPub date: 2011 Apr 17.
PMID: 21499250
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Heritable variation of ERBB2 and breast cancer risk.
Authors: Breyer JP, Sanders ME, Airey DC, Cai Q, Yaspan BL, Schuyler PA, Dai Q, Boulos F, Olivares MG, Bradley KM, Gao YT, Page DL, Dupont WD, Zheng W, Smith JR
Source: Cancer Epidemiol Biomarkers Prev, 2009 Apr;18(4), p. 1252-8.
EPub date: 2009 Mar 31.
PMID: 19336545
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A two-stage case-control study of EGFR polymorphisms and breast cancer risk.
Authors: Hong YS, Deming SL, Gao YT, Long JR, Shu XO, Cai Q, Lu W, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2009 Feb;18(2), p. 680-3.
EPub date: 2009 Feb 3.
PMID: 19190167
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Genetic polymorphisms of metastasis suppressor gene NME1 and breast cancer survival.
Authors: Qu S, Long J, Cai Q, Shu XO, Cai H, Gao YT, Zheng W
Source: Clin Cancer Res, 2008 Aug 1;14(15), p. 4787-93.
PMID: 18676749
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Circulating transforming growth factor-beta-1 and breast cancer prognosis: results from the Shanghai Breast Cancer Study.
Authors: Grau AM, Wen W, Ramroopsingh DS, Gao YT, Zi J, Cai Q, Shu XO, Zheng W
Source: Breast Cancer Res Treat, 2008 Nov;112(2), p. 335-41.
EPub date: 2007 Dec 13.
PMID: 18075785
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ERBB2 genetic polymorphism and breast cancer risk in Chinese women: a population-based case-control study.
Authors: Qu S, Cai Q, Gao YT, Lu W, Cai H, Su Y, Wang SE, Shu XO, Zheng W
Source: Breast Cancer Res Treat, 2008 Jul;110(1), p. 169-76.
EPub date: 2007 Aug 9.
PMID: 17687647
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Energy balance, insulin resistance biomarkers, and breast cancer risk.
Authors: Fair AM, Dai Q, Shu XO, Matthews CE, Yu H, Jin F, Gao YT, Zheng W
Source: Cancer Detect Prev, 2007;31(3), p. 214-9.
EPub date: 2007 Jul 23.
PMID: 17646056
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Dietary patterns and breast cancer risk in the shanghai breast cancer study.
Authors: Cui X, Dai Q, Tseng M, Shu XO, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2007 Jul;16(7), p. 1443-8.
EPub date: 2007 Jul 10.
PMID: 17623805
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Haplotype analysis of CYP11A1 identifies promoter variants associated with breast cancer risk.
Authors: Yaspan BL, Breyer JP, Cai Q, Dai Q, Elmore JB, Amundson I, Bradley KM, Shu XO, Gao YT, Dupont WD, Zheng W, Smith JR
Source: Cancer Res, 2007 Jun 15;67(12), p. 5673-82.
PMID: 17575134
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Expression patterns of the ATM gene in mammary tissues and their associations with breast cancer survival.
Authors: Ye C, Cai Q, Dai Q, Shu XO, Shin A, Gao YT, Zheng W
Source: Cancer, 2007 May 1;109(9), p. 1729-35.
PMID: 17366603
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Association of serum concentration of organochlorine pesticides with dietary intake and other lifestyle factors among urban Chinese women.
Authors: Lee SA, Dai Q, Zheng W, Gao YT, Blair A, Tessari JD, Tian Ji B, Shu XO
Source: Environ Int, 2007 Feb;33(2), p. 157-63.
EPub date: 2006 Oct 18.
PMID: 17055057
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Energy balance and breast cancer risk.
Authors: Malin A, Matthews CE, Shu XO, Cai H, Dai Q, Jin F, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2005 Jun;14(6), p. 1496-501.
PMID: 15941962
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Association of cyclin D1 genotype with breast cancer risk and survival.
Authors: Shu XO, Moore DB, Cai Q, Cheng J, Wen W, Pierce L, Cai H, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2005 Jan;14(1), p. 91-7.
PMID: 15668481
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Insulin-like growth factor-I, soy protein intake, and breast cancer risk.
Authors: Sanderson M, Shu XO, Yu H, Dai Q, Malin AS, Gao YT, Zheng W
Source: Nutr Cancer, 2004;50(1), p. 8-15.
PMID: 15572292
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Oral contraceptive use and breast cancer risk: modification by NAD(P)H:quinone oxoreductase (NQO1) genetic polymorphisms.
Authors: Fowke JH, Shu XO, Dai Q, Jin F, Cai Q, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2004 Aug;13(8), p. 1308-15.
PMID: 15298951
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Genetic polymorphisms in the human growth hormone-1 gene (GH1) and the risk of breast carcinoma.
Authors: Ren Z, Cai Q, Shu XO, Cai H, Cheng JR, Wen WQ, Gao YT, Zheng W
Source: Cancer, 2004 Jul 15;101(2), p. 251-7.
PMID: 15241820
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Joint effect of insulin-like growth factors and sex steroids on breast cancer risk.
Authors: Yu H, Shu XO, Li BD, Dai Q, Gao YT, Jin F, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2003 Oct;12(10), p. 1067-73.
PMID: 14578144
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Dietary calcium intake and breast cancer risk among Chinese women in Shanghai.
Authors: Boyapati SM, Shu XO, Jin F, Dai Q, Ruan Z, Gao YT, Zheng W
Source: Nutr Cancer, 2003;46(1), p. 38-43.
PMID: 12925302
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Urinary phytoestrogen excretion and breast cancer risk: evaluating potential effect modifiers endogenous estrogens and anthropometrics.
Authors: Dai Q, Franke AA, Yu H, Shu XO, Jin F, Hebert JR, Custer LJ, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2003 Jun;12(6), p. 497-502.
PMID: 12814993
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Plasma sex steroid hormones and breast cancer risk in Chinese women.
Authors: Yu H, Shu XO, Shi R, Dai Q, Jin F, Gao YT, Li BD, Zheng W
Source: Int J Cancer, 2003 May 20;105(1), p. 92-7.
PMID: 12672036
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Occupations and breast cancer risk among Chinese women in urban Shanghai.
Authors: Gardner KM, Ou Shu X, Jin F, Dai Q, Ruan Z, Thompson SJ, Hussey JR, Gao YT, Zheng W
Source: Am J Ind Med, 2002 Oct;42(4), p. 296-308.
PMID: 12271477
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Urinary excretion of phytoestrogens and risk of breast cancer among Chinese women in Shanghai.
Authors: Dai Q, Franke AA, Jin F, Shu XO, Hebert JR, Custer LJ, Cheng J, Gao YT, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2002 Sep;11(9), p. 815-21.
PMID: 12223424
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Consumption of animal foods, cooking methods, and risk of breast cancer.
Authors: Dai Q, Shu XO, Jin F, Gao YT, Ruan ZX, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2002 Sep;11(9), p. 801-8.
PMID: 12223422
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Insulin-like growth factors and breast cancer risk in Chinese women.
Authors: Yu H, Jin F, Shu XO, Li BD, Dai Q, Cheng JR, Berkel HJ, Zheng W
Source: Cancer Epidemiol Biomarkers Prev, 2002 Aug;11(8), p. 705-12.
PMID: 12163322
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Weight at birth and adolescence and premenopausal breast cancer risk in a low-risk population.
Authors: Sanderson M, Shu XO, Jin F, Dai Q, Ruan Z, Gao YT, Zheng W
Source: Br J Cancer, 2002 Jan 7;86(1), p. 84-8.
PMID: 11857016
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Population-based case-control study of soyfood intake and breast cancer risk in Shanghai.
Authors: Dai Q, Shu XO, Jin F, Potter JD, Kushi LH, Teas J, Gao YT, Zheng W
Source: Br J Cancer, 2001 Aug 3;85(3), p. 372-8.
PMID: 11487268
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Abortion history and breast cancer risk: results from the Shanghai Breast Cancer Study.
Authors: Sanderson M, Shu XO, Jin F, Dai Q, Wen W, Hua Y, Gao YT, Zheng W
Source: Int J Cancer, 2001 Jun 15;92(6), p. 899-905.
PMID: 11351314
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