Wky Rat Genetic Model for Breast Cancer Susceptibility

描述（由申请人提供）：Mcs 5是乳腺癌易感性大鼠数量性状基因座（QTL），包含至少三个亚基因座（Mcs 5a、-5b和-5c），这些亚基因座对易感性有贡献，并显示彼此间的上位性相互作用。我们已经表明，Mcs 5a，一个非乳腺细胞自主基因座，是一个复合QTL，具有两个相互作用的元素，差异控制Fbxo 10在T细胞。这两种元素的人类同源物中的SNP均显示与女性乳腺癌风险相关（n E 12，000）。该延续提案的目标是通过表征Mcs 5c和Mcs 5 b来进一步研究Mcs 5 QTL。第一个目标将集中在遗传和生物学研究使用现有的同源重组大鼠模型的Mcs 5c和Mcs 5 b基因座。这两个基因座将被精细定位到200 Kb以下的区间。我们还将确定这些基因座是否以乳腺细胞自主的方式起作用。接下来，将通过比较WKy和WF等位基因来注释Mcs 5 b和Mcs 5c的减少的基因组间隔，以鉴定这些基因座内作为其易感性表型基础的明确定义的候选元件。将确定每个基因座对乳腺癌易感性发挥作用的基因和器官/细胞类型。集中于所鉴定的细胞类型，将注释这两个基因座处的WKy和WF等位基因之间的进一步遗传和表观遗传差异。待使用的方法的实例包括：ChIP-CHIP;染色体构象捕获测定（3C）;鉴定为潜在功能的重测序区域。Mcs 5c和Mcs 5 b的选定候选基因座将通过产生和表征适当的基因工程大鼠模型来验证。该项目将鉴定和表征新的乳腺癌风险相关等位基因。初步数据和以前的结果与Mcs 5a表明，这些等位基因的人类同源物也可能有助于人类乳腺癌的风险。最后，Mcs 5c和Mcs 5 b等位基因的功能研究将确定乳腺癌病因学中涉及的独特途径。公共卫生相关性：该项目与公共卫生直接相关，因为它将调查乳腺癌病因学遗传成分的独特方面。它也有可能为人类乳腺癌提供风险标志物。从广义上讲，它也可能为解释常见疾病的全基因组关联研究结果提供新的见解。

DESCRIPTION (provided by applicant): Mcs5 is a mammary carcinoma susceptibility rat quantitative trait locus (QTL) that contains at least three sub-loci (Mcs5a, -5b, and -5c) which contribute to susceptibility and show epistatic interactions with one another. We have shown that Mcs5a, a non-mammary gland cell autonomous locus, is a compound QTL having two interacting elements which differentially control Fbxo10 in T cells. SNPs in human homologues of both of these two elements have each been shown to associate with breast cancer risk in women (n E 12,000). The goal of this continuation proposal is to further study the Mcs5 QTL by characterizing Mcs5c and Mcs5b. The first aim will focus on genetic and biological studies using existing congenic recombinant rat models for the Mcs5c and Mcs5b loci. Both loci will be fine mapped to intervals below 200 Kb. We will also determine if these loci act in a mammary cell autonomous manner. Next, the reduced genomic intervals of Mcs5b and Mcs5c will be annotated by comparing the WKy and WF alleles in order to identify well-defined candidate elements within these loci which underlie their susceptibility phenotypes. The genes and organ/cell type through which each locus exerts its effect on mammary cancer susceptibility will be determined. Focusing on the identified cell type, further genetic and epigenetic differences between the WKy and WF alleles at these two loci will be annotated. Examples of methods to be used include: ChIP-CHIP; chromosome conformation capture assay (3C); resequencing areas identified as potentially functional. Selected candidate loci for Mcs5c and Mcs5b will be validated by producing and characterizing appropriate genetically engineered rat models. This project will identify and characterize novel mammary cancer risk associated alleles. Preliminary data and previous results with Mcs5a suggest that human homologues of these alleles may also contribute to breast cancer risk in humans. Finally, functional studies of the Mcs5c and Mcs5b alleles will define unique pathways involved in the etiology of breast cancer. PUBLIC HEALTH RELEVANCE: This project is directly relative to public health in that it will investigate unique aspects of the genetic component of breast cancer etiology. It is also possible that it will provide risk markers for human breast cancer. Broadly, it will also likely provide new insights for interpretation of the results of genome-wide association studies for common diseases.