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Grant Details

Grant Number: 7R01CA105197-04 Interpret this number
Primary Investigator: Egan, Kathleen
Organization: H. Lee Moffitt Cancer Ctr & Res Inst
Project Title: Gene Interactions, Estrogen, and Risk of Breast Cancer
Fiscal Year: 2006
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Abstract

DESCRIPTION (provided by applicant): Polymorphic variation in genes regulating estrogen synthesis, bioavailability and metabolism may contribute to the individual risk for breast cancer. Few previous studies had statistical power to examine complex interactions among these genes. Moreover, the majority of previous (mostly null) studies considered only single genetic markers in candidate genes with the possibility that important relationships were not detected. In this application we are proposing to study the contribution of variation in the estrogen genes to breast cancer, using existing data and materials collected in the Collaborative Breast Cancer Study, a large, population-based case-control study conducted in the US. Over a 4-year period (1997-2001), more than 4,400 women with a recent diagnosis of breast cancer and 3,800 population-based controls completed a telephone interview on breast cancer risk factors and provided buccal mucosal DNA for genetic research. Response rates in cases (72%) and controls (63%) were high for this type of research, and the average yield of DNA was adequate for typing several hundred variants. All of the anonymized samples have been extracted for DNA, aliquoted and stored at -70 x for this planned research. We are now proposing to test current hypotheses linking critical genes in estrogen biosynthesis and metabolism to the risk for breast cancer. Genes included in this proposal are involved at key branch points in estrogen synthesis (STAR, CYP11A1, HSD 3B, CYP17, CYP19, HSD17B , TNF, IL6, PPAR G, STS), in steroid signaling (ESR1, ESR2, PGR, SHBG, AIB1), and in estrogen metabolism (CYP1A1, CYP1A2, CYPIB1, CYP3A4) and inactivation (SULTs, UGTs, COMT, NQOs, GSTs). Using the best available information, we propose to study both known functional variants, and also single nucleotide polymorphisms in other unlinked regions of genes to increase the chance of detecting associations. Several of the genes are novel to this application, and we propose detailed genetic analyses using CEPH pedigrees to determine haplotype structures in this population. Interactions among variants will be tested using statistical procedures designed to detect high-order genetic interaction. This is one of the largest assembled resources of DNA and epidemiologic data for research in breast cancer. The work proposed in this application will provide timely and cost-effective new information on the genetic pathways to breast cancer that may prove relevant to screening, detection, and more targeted treatment strategies.

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Publications

A multistage genetic association study identifies breast cancer risk loci at 10q25 and 16q24.
Authors: Higginbotham KS, Breyer JP, McReynolds KM, Bradley KM, Schuyler PA, Plummer WD, Freudenthal ME, Trentham-Dietz A, Newcomb PA, Parl FF, Sanders ME, Page DL, Egan KM, Dupont WD, Smith JR
Source: Cancer Epidemiol Biomarkers Prev, 2012 Sep;21(9), p. 1565-73.
EPub date: 2012 Jul 17.
PMID: 22806168
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A multistage association study identifies a breast cancer genetic locus at NCOA7.
Authors: Higginbotham KS, Breyer JP, Bradley KM, Schuyler PA, Plummer WD Jr, Freudenthal ME, Trentham-Dietz A, Newcomb PA, Sanders ME, Page DL, Parl FF, Egan KM, Dupont WD, Smith JR
Source: Cancer Res, 2011 Jun 1;71(11), p. 3881-8.
EPub date: 2011 May 24.
PMID: 21610108
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Replication and functional genomic analyses of the breast cancer susceptibility locus at 6q25.1 generalize its importance in women of chinese, Japanese, and European ancestry.
Authors: Cai Q, Wen W, Qu S, Li G, Egan KM, Chen K, Deming SL, Shen H, Shen CY, Gammon MD, Blot WJ, Matsuo K, Haiman CA, Khoo US, Iwasaki M, Santella RM, Zhang L, Fair AM, Hu Z, Wu PE, Signorello LB, Titus-Ernstoff L, Tajima K, Henderson BE, Chan KY, Kasuga Y, Newcomb PA, Zheng H, Cui Y, Wang F, Shieh YL, Iwata H, Le Marchand L, Chan SY, Shrubsole MJ, Trentham-Dietz A, Tsugane S, Garcia-Closas M, Long J, Li C, Shi J, Huang B, Xiang YB, Gao YT, Lu W, Shu XO, Zheng W
Source: Cancer Res, 2011 Feb 15;71(4), p. 1344-55.
EPub date: 2011 Feb 8.
PMID: 21303983
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Association of COMT haplotypes and breast cancer risk in caucasian women.
Authors: Peterson NB, Trentham-Dietz A, Garcia-Closas M, Newcomb PA, Titus-Ernstoff L, Huang Y, Chanock SJ, Haines JL, Egan KM
Source: Anticancer Res, 2010 Jan;30(1), p. 217-20.
PMID: 20150638
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Association of CYP1B1 haplotypes and breast cancer risk in Caucasian women.
Authors: Huang Y, Trentham-Dietz A, García-Closas M, Newcomb PA, Titus-Ernstoff L, Hampton JM, Chanock SJ, Haines JL, Egan KM
Source: Cancer Epidemiol Biomarkers Prev, 2009 Apr;18(4), p. 1321-3.
EPub date: 2009 Mar 17.
PMID: 19293312
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Tea consumption and risk of breast cancer.
Authors: Kumar N, Titus-Ernstoff L, Newcomb PA, Trentham-Dietz A, Anic G, Egan KM
Source: Cancer Epidemiol Biomarkers Prev, 2009 Jan;18(1), p. 341-5.
PMID: 19124518
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Whole-genome amplification of oral rinse self-collected DNA in a population-based case-control study of breast cancer.
Authors: Liang X, Trentham-Dietz A, Titus-Ernstoff L, Newcomb PA, Welch RA, Hutchinson AA, Hampton JM, Sutcliffe CB, Haines JL, Egan KM
Source: Cancer Epidemiol Biomarkers Prev, 2007 Aug;16(8), p. 1610-4.
PMID: 17684135
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Genetic variation in TP53 and risk of breast cancer in a population-based case control study.
Authors: Sprague BL, Trentham-Dietz A, Garcia-Closas M, Newcomb PA, Titus-Ernstoff L, Hampton JM, Chanock SJ, Haines JL, Egan KM
Source: Carcinogenesis, 2007 Aug;28(8), p. 1680-6.
EPub date: 2007 Apr 21.
PMID: 17449902
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