|Grant Number:||5R01CA104021-05 Interpret this number|
|Primary Investigator:||Hall, Per|
|Project Title:||Genetic Determinants of Postmenopausal Breast Cancer|
DESCRIPTION (provided by applicant): A central concern regarding the widespread use of menopausal hormones is the increased breast cancer risk as recently described in several large studies. Since many women nevertheless have considerable benefit from this therapy, mainly alleviation of menopausal symptoms, it would be of outmost value if we were able to identify those women in whom the use of menopausal hormones should be discouraged due to an unacceptably increased breast cancer risk. Since this treatment could be seen as a representation of any hormonal exposures, it can serve as a model for how other hormonal factors, such as age at menopause and BMI, interact with breast cancer susceptibility genes. We will study genetic variation in pathways that regulate estrogen exposure (estrogen metabolism pathway) and regulate response to estrogen exposure (receptors and associated proteins, transcription cofactors and responsive genes) influence the risk of breast cancer. Further, we want to investigate how the influence of this genetic variation is affected by intake of exogenous hormones. The influence of estrogen in the breast tissue is mediated via one of its receptors, estrogen receptor a (ER) and transcription induced by the ER is dependent on co-regulators. We have experimentally, using T47D cells and expression arrays, identified estrogen responsive genes and genes that are associated with ER status in primary breast cancers. We have also constructed a database of gene expression data that integrates all six publicly available and some unpublished breast cancer microarray datasets. The purpose of the database is to facilitate the mining of genes with robust associations, with clinicopathological variables in human breast cancer. We propose a systematic approach for gene association study that first employs bioinformatics and genomic approaches to expand the number of likely candidate genes from several to hundreds. In addition, by using haplotype-tagging SNPs (ht-SNPs), we reduce the genotyping load by approximately 75%, while retaining thorough characterization of each gene under evaluation.
Comprehensive Analysis Of The Atm, Chek2 And Erbb2 Genes In Relation To Breast Tumour Characteristics And Survival: A Population-based Case-control And Follow-up Study
Authors: Einarsdóttir,K. , Rosenberg,L.U. , Humphreys,K. , Bonnard,C. , Palmgren,J. , Li,Y. , Chia,K.S. , Liu,E.T. , Hall,P. , Liu,J. , et al. .
Source: Breast Cancer Research : Bcr, 2006; 8(6), p. R67.
Esr1 And Egf Genetic Variation In Relation To Breast Cancer Risk And Survival
Authors: Einarsdóttir,K. , Darabi,H. , Li,Y. , Low,Y.L. , Li,Y.Q. , Bonnard,C. , Sjölander,A. , Czene,K. , Wedrén,S. , Liu,E.T. , et al. .
Source: Breast Cancer Research : Bcr, 2008; 10(1), p. R15.
Association Of Esr1 Gene Tagging Snps With Breast Cancer Risk
Authors: Dunning A.M. , Healey C.S. , Baynes C. , Maia A.T. , Scollen S. , Vega A. , Rodríguez R. , Barbosa-Morais N.L. , Ponder B.A. , SEARCH , et al. .
Source: Human Molecular Genetics, 2009-03-15 00:00:00.0; 18(6), p. 1131-9.
Newly Discovered Breast Cancer Susceptibility Loci On 3p24 And 17q23.2
Authors: Ahmed S. , Thomas G. , Ghoussaini M. , Healey C.S. , Humphreys M.K. , Platte R. , Morrison J. , Maranian M. , Pooley K.A. , Luben R. , et al. .
Source: Nature Genetics, 2009 May; 41(5), p. 585-90.
Five Polymorphisms And Breast Cancer Risk: Results From The Breast Cancer Association Consortium
Authors: Gaudet M.M. , Milne R.L. , Cox A. , Camp N.J. , Goode E.L. , Humphreys M.K. , Dunning A.M. , Morrison J. , Giles G.G. , Severi G. , et al. .
Source: Cancer Epidemiology, Biomarkers & Prevention : A Publication Of The American Association For Cancer Research, Cosponsored By The American Society Of Preventive Oncology, 2009 May; 18(5), p. 1610-6.
Multi-variant Pathway Association Analysis Reveals The Importance Of Genetic Determinants Of Estrogen Metabolism In Breast And Endometrial Cancer Susceptibility
Authors: Low,Y.L. , Li,Y. , Humphreys,K. , Thalamuthu,A. , Darabi,H. , Wedrén,S. , Bonnard,C. , Czene,K. , Iles,M.M. , Heikkinen,T. , et al. .
Source: Plos Genetics, 2010 Jul; 6(7), p. e1001012.
Hundreds Of Variants Clustered In Genomic Loci And Biological Pathways Affect Human Height
Authors: Lango Allen H. , Estrada K. , Lettre G. , Berndt S.I. , Weedon M.N. , Rivadeneira F. , Willer C.J. , Jackson A.U. , Vedantam S. , Raychaudhuri S. , et al. .
Source: Nature, 2010-10-14 00:00:00.0; 467(7317), p. 832-8.
Thirty New Loci For Age At Menarche Identified By A Meta-analysis Of Genome-wide Association Studies
Authors: Elks C.E. , Perry J.R. , Sulem P. , Chasman D.I. , Franceschini N. , He C. , Lunetta K.L. , Visser J.A. , Byrne E.M. , Cousminer D.L. , et al. .
Source: Nature Genetics, 2010 Dec; 42(12), p. 1077-85.
Swedish Population Substructure Revealed By Genome-wide Single Nucleotide Polymorphism Data
Authors: Salmela,E. , Lappalainen,T. , Liu,J. , Sistonen,P. , Andersen,P.M. , Schreiber,S. , Savontaus,M.L. , Czene,K. , Lahermo,P. , Hall,P. , et al. .
Source: Plos One, 2011; 6(2), p. e16747.
Genetic Risk And A Primary Role For Cell-mediated Immune Mechanisms In Multiple Sclerosis
Authors: International Multiple Sclerosis Genetics Consortium , Wellcome Trust Case Control Consortium 2 , Sawcer,S. , Hellenthal,G. , Pirinen,M. , Spencer,C.C. , Patsopoulos,N.A. , Moutsianas,L. , Dilthey,A. , Su,Z. , et al. .
Source: Nature, 2011-08-11 00:00:00.0; 476(7359), p. 214-9.
Analysis Of Immune-related Loci Identifies 48 New Susceptibility Variants For Multiple Sclerosis
Authors: International Multiple Sclerosis Genetics Consortium (IMSGC) , Beecham A.H. , Patsopoulos N.A. , Xifara D.K. , Davis M.F. , Kemppinen A. , Cotsapas C. , Shah T.S. , Spencer C. , Booth D. , et al. .
Source: Nature Genetics, 2013 Nov; 45(11), p. 1353-60.