Discovery, Biology and Risk of Inherited Variants in Breast Cancer

描述(申请人提供)：我们提出了一个综合的多PI项目，以系统地发现和复制与乳腺癌相关的其他常见遗传变异，评估它们的生物学意义，并开发基于证据的评估，以评估使用这些变异的预测算法的临床有效性，以及它们转化为临床实践的适宜性。在分项目1中，我们将结合(A)主要的全球乳腺癌研究中心的资源，共计15,000个病例；(B)三个先前存在的联合体，再加上48,000多个病例，以提供复制阶段所需的大样本需求。我们将与为亚裔和非裔美国女性的乳腺癌进行GWA的主要财团合作，精细绘制相关的基因座图。在子项目2中，我们将进行一系列调查，以(A)通过测量24,000个RNA转录本在乳腺肿瘤组织和正常组织中的表达，从而分配一个基因功能给每个复制的风险变体；(B)通过确定表达变化可以与特定生殖系风险变体相关联的基因网络；通过使用染色体构象捕获分析来检查相关的基因间隔区是否以使其能够与远程精灵区域接触的方式在物理上折叠。我们还将(B)在乳腺形态发生和肿瘤发生的三维模型中研究(A)中涉及的基因功能的丧失或获得是否会在体外改变乳腺形态发生和肿瘤发生的表型。在子项目3中，我们将开发乳腺癌预测模型，该模型可用于根据乳腺癌风险对女性进行分层。我们将尝试通过重新分析Gwas数据来发现基因-基因相互作用，我们将使用现有的最大一组前瞻性研究，系统地检查全基因组范围内显著的基因变异，以影响已建立的乳腺癌风险因素的修饰。我们将开发和完善包含生殖系风险因素和已建立的非遗传风险因素的风险模型，并在乳腺癌家族风险较高的女性队列中对这些因素进行评估(以具体解决因乳腺癌家族史而处于高风险状态的女性的临床需求)。最后，我们将分析主要乳腺癌一级预防试验的数据，以解决我们的预测模型中他莫昔芬的保护作用是否会因风险状况而改变的问题，这些数据与已知高危女性的化学预防的临床决策直接相关。

DESCRIPTION (provided by applicant): We propose an integrated multiple-PI Project to systematically discover and replicate additional common genetic variants associated with breast cancer, assess their biological significance, and develop evidence based assessments of the clinical validity of prediction algorithms using these variants, and their suitability for translation into clinical practice. In sub-Project 1 we will combine the resources of (a) major GWAS for breast cancer amounting to >15,000 cases and (b) three pre-existing Consortia with over 48,000 additional cases to provide the large sample size needs necessary in the replication phase of GWAS. We will fine map the associated loci in collaboration with the major Consortia conducting GWAS for breast cancer in Asian and African-American women. In sub-Project 2 we will conduct a series of investigations to (a) assign a gene function to each replicated risk variant by measuring expression of 24,000 RNA transcripts in breast tumor tissue and normal tissue, from women for whom we also have an lllumina 540 GWAS available; by identifying networks of genes in which alterations of expression can be linked to specific germline risk variants; and by using Chromosomal Conformation Capture assays to examine whether associated intergenic regions fold physically in a way that brings them into contact with distant genie regions. We will also (b) examine whether loss or gain of function of the genes implicated in (a) in breast epithelial cells or stromal cells alter phenotypes in vitro in a 3-D model of breast morphogenesis and oncogenesis. In sub- Project 3, we will develop breast cancer prediction models that can be used to stratify women according to breast cancer risk. We will attempt to discover gene-gene interactions by reanalyzing the GWAS data, and we will systematically examine the genome-wide significant gene variants for effect modification by established breast cancer risk factors, using the largest set of prospective studies available. We will develop and refine risk models that incorporate both the germline risk factors and the established non-genetic risk factors, and also assess these in a cohort of women with higher familial risk of breast cancer (to specifically address the clinical needs of women at high risk due to a strong family history of breast cancer). Finally, we will analyze data from the major trials of primary prevention of breast cancer to address the question of whether the protective effect of tamoxifen is altered by risk status for our prediction models, data with a direct bearing on clinical decision-making with respect to chemoprevention for women at known high risk.