This application is one of four submitted concurrently to allow large-scale analyses of breast and prostate cancer risk in relation to genetic polymorphisms and gene-environment interactions that affect hormone metabolism. These proposals combine the resources of six large prospective cohorts from the American Cancer Society (CPS-II study), Harvard University (Harvard Cohort Studies), the IARC (EPIC study), and the Universities of Hawaii and Southern California (Multiethnic cohort); in addition, two NCI intramural cohorts (PLCO and ATBC studies) will participate. The proposed study is unique in having prospective plasma samples, genetic material, anthropometric measurements, and extensive questionnaire data on diet, physical activity, exogenous hormone use, smoking, and other lifestyle factors from over 790,000 men and women. Because of the scope and collaborative nature of this consortium, simultaneous investigation of genetic predisposition and lifestyle factors is possible, to clarify the inter-relationships between, and the relative importance of, genetic and hormonal risk factors. Specifically, this study will define SNPs and haplotypes in steroid hormone metabolizing genes, genes in the IGF pathway, and related receptor proteins. These candidate genes will be resequenced in 96 cases of advanced breast cancer, and 96 cases of advanced prostate cancer, chosen from the European, African, Latino, Japanese, and Hawaiian-origin ethnic groups. Haplotype tag SNPs will be selected after genotyping of a larger number of SNPs from a collection of 768 samples from the multigenerational CEPH (Centre d'Etude du Polymorphisme Humain) pedigrees and human diversity collection, by the Whitehead Institute for Genome Research and CEPH, and will rapidly be made publicly available. The interaction of genetic variants with hormonal, lifestyle and anthropometric factors known to be associated with breast and prostate cancer will be examined. In a subset of studies, the association of these variants with markers of breast and prostate cancer risk (i.e. plasma steroid hormone levels and IGF-1 levels) will be investigated. Projects developed within the Cohort Consortium will foster continuing interactions between the genomic and epidemiologic research communities and help integrate the rapid advances in genomic research into large-scale epidemiologic studies. The ultimate goal is to provide the foundation for reducing the public health burden of these cancers.
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