Wky Rat Genetic Model for Breast Cancer Susceptibility

描述(申请人提供)：Mcs5是一个乳腺癌易感性大鼠数量性状基因座(QTL)，它至少包含三个亚位点(Mcs5a、-5b和-5c)，它们与易感性有关，并表现出上位性相互作用。我们已经证明，Mcs5a是一个非乳腺细胞自主基因，是一个含有两个相互作用的元件的复合QTL，这两个元件在T细胞中差异地控制Fbxo10。这两种元素在人类同系物中的SNP都被证明与女性乳腺癌风险有关(n E 12,000)。这一继续方案的目的是通过鉴定Mcs5c和Mcs5b来进一步研究Mcs5的QTL。第一个目标将侧重于利用现有的Mcs5c和Mcs5b基因座的同源重组大鼠模型进行遗传和生物学研究。这两个基因座都将被精细定位到200kb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发挥作用。接下来，将通过比较WKY和WF等位基因来注释Mcs5b和Mcs5c缩短的基因组间隔，以便识别这些基因座中明确定义的候选元件，这些候选元件是其易感表型的基础。将确定每个基因和器官/细胞类型通过哪些基因和器官/细胞类型影响乳腺癌的易感性。聚焦于已识别的细胞类型，将进一步说明这两个基因座的WKY和WF等位基因之间的遗传和表观遗传学差异。要使用的方法的例子包括：芯片；染色体构象捕获分析(3C)；重新测序被确定为潜在功能的区域。选定的Mcs5c和Mcs5b候选基因座将通过制造和鉴定适当的基因工程大鼠模型来验证。该项目将识别和表征新的乳腺癌风险相关等位基因。初步数据和Mcs5a之前的结果表明，这些等位基因的人类同源物也可能导致人类患乳腺癌的风险。最后，对Mcs5c和Mcs5b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，因为它将研究乳腺癌病因学中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记物。总的来说，它还可能为解释常见疾病全基因组关联研究的结果提供新的见解。

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.