Epidemiologic Studies

总结。子项目3(流行病学：乳腺癌的基因、可改变的风险因素和风险预测)将扩展现有的全基因组关联研究(GWAS)，并通过表征新发现的常见乳腺癌风险等位基因、已知的乳腺癌风险因素和乳腺癌发病率之间的关系，扩展本申请的子项目1中的额外发现工作。这个子项目将通过建议乳腺癌病因学的特定生物学机制(目标1-3)和评估遗传风险预测模型在各种环境中的临床有效性和实用性(目标4-6)，加速将GWAS的研究成果转化为临床和公共卫生实践。 子项目包括六个具体目标：1)为与以下因素相互作用的新的基因座开展全球气候分析 其中包括：1)评估已知的乳腺癌等位基因；2)评估已知乳腺癌风险等位基因之间的基因-基因交互作用；3)评估已知乳腺癌风险等位基因与既定风险因素之间的基因-环境交互作用；4)构建和比较结合了多个乳腺癌等位基因和已知风险因素的信息的风险预测算法的临床有效性；5)评估这些算法在高危家庭中的性能；以及6)评估预防性三苯氧胺治疗的基因修改。

Summary. Sub-Project 3 (Epidemiology: genes, modifiable risk factors, and risk prediction for breast cancer) will extend existing genome-wide association studies (GWAS) as well as the additional discovery efforts in Sub-Project 1 of this application by characterizing the relationships among newly-discovered common breast cancer risk alleles, known breast cancer risk factors, and breast cancer incidence. This Sub-Project will accelerate the translation of GWAS findings to clinical and public health practice by suggesting particular biologic mechanisms for breast cancer etiology (Aims 1-3) and by evaluating the clinical validity and utility of genetic risk prediction models in a variety of settings (Aims 4-6). The Sub-Project encompasses six specific aims: 1) Conduct a GWAS for new loci that interact with other, known breast cancer alleles; 2) assess gene-gene interactions among known breast cancer risk alleles; 3) assess gene-environment interactions between known breast cancer risk alleles and established risk factors, most notably modifiable exposures such as postmenopausal hormone therapy; 4) construct and compare the clinical validity of risk prediction algorithms that combine information on multiple breast cancer alleles and known risk factors; 5) evaluate the performance of these algorithms in high-risk families; and 6) assess genetic modification of prophylactic tamoxifen treatment.