We propose to build a collaborative database of Genome-Wide Association Studies (GWAS) of breast cancer with over 15,000 cases of European ancestry, and appropriate controls, and impute >2.5 million imputed HapmapS SNPs for these cases and controls. We will then rank all genotyped and imputed SNPs based their P values for association with (a) total breast cancer (b) breast cancer at age <50 (primarily based on 3,200 cases and 3,200 controls scanned in the Breast Cancer Family Registry (BCFR)) and (c) women with ER-negative breast cancer (primarily based on 1,600 cases and 1,600 controls scanned in the NCI Breast and Prostate Cancer Cohort Consortium (BPC3) Based on these results we will perform replication studies in two large-scale Consortia (a) cohorts in the BCP3 and (b) case-control studies in the Breast Cancer Association Consortium (BCAC). In the BPC3 we propose to expand the current six component cohorts (13,500 cases and an equal number of controls) by collaborating with the Women's Health Initiative (4,500 cases and 4,500 controls) to increase the BPC3 sample size to 18,000 cases and 18,000 controls. To narrow the interval of linkage disequilibrium observed at each locus we will collaborate with large pooled GWAS of breast cancer in women with African ancestry (n=2,500 cases and 2,500 controls) and Asian ancestry (n=3,500 cases and 3,500 controls). Building on this trans-ethnic collaborative effort and on the resequencing data from the 1,000 Genomes Project, we will choose SNPs for fine mapping of the loci identified in the previous aims, in 10,000 further European ancestry cases and 10,000 controls, and an additional 3,500 Asian cases and 3,500 controls, in order to narrow the number of variants for which evidence of function will be sought in sub-Project 2.
This project will aid in the systematic discovery and replication of germline genetic variants that are associated with risk of breast cancer. Initially a genetic locus will be identified, and then from a large number of variants at the locus, one or a small number of variants with the strongest associations will be identified. These can be investigated in Project 2 of this proposal and may eventually lead to better prevention and treatment strategies for breast cancer, which is expected to kill over 40,000 U.S. women in 2009. These variants will also be examined for gene-gene interaction, gene-environment interaction, and their contribution to risk prediction algorithms in Project 3.
|Gao, Guimin; Pierce, Brandon L; Olopade, Olufunmilayo I et al. (2017) Trans-ethnic predicted expression genome-wide association analysis identifies a gene for estrogen receptor-negative breast cancer. PLoS Genet 13:e1006727|
|Cuzick, Jack; Brentnall, Adam R; Segal, Corrinne et al. (2017) Impact of a Panel of 88 Single Nucleotide Polymorphisms on the Risk of Breast Cancer in High-Risk Women: Results From Two Randomized Tamoxifen Prevention Trials. J Clin Oncol 35:743-750|
|Feng, Yen-Chen Anne; Cho, Kelly; Lindstrom, Sara et al. (2017) Investigating the genetic relationship between Alzheimer's disease and cancer using GWAS summary statistics. Hum Genet 136:1341-1351|
|Zuber, Verena; Bettella, Francesco; Witoelar, Aree et al. (2017) Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer. BMC Genomics 18:270|
|Milne, Roger L (see original citation for additional authors) (2017) Identification of ten variants associated with risk of estrogen-receptor-negative breast cancer. Nat Genet 49:1767-1778|
|Shimelis, Hermela; Mesman, Romy L S; Von Nicolai, Catharina et al. (2017) BRCA2 Hypomorphic Missense Variants Confer Moderate Risks of Breast Cancer. Cancer Res 77:2789-2799|
|Muranen, Taru A; Greco, Dario; Blomqvist, Carl et al. (2017) Genetic modifiers of CHEK2*1100delC-associated breast cancer risk. Genet Med 19:599-603|
|Ugalde-Morales, Emilio; Li, Jingmei; Humphreys, Keith et al. (2017) Common shared genetic variation behind decreased risk of breast cancer in celiac disease. Sci Rep 7:5942|
|Wang, Jun; Heng, Yujing J; Eliassen, A Heather et al. (2017) Alcohol consumption and breast tumor gene expression. Breast Cancer Res 19:108|
|Scannell Bryan, Molly; Argos, Maria; Andrulis, Irene L et al. (2017) Limited influence of germline genetic variation on all-cause mortality in women with early onset breast cancer: evidence from gene-based tests, single-marker regression, and whole-genome prediction. Breast Cancer Res Treat 164:707-717|
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