Characterizing a Breast Cancer Modifier Locus That Associates with Human Risk

描述（由申请人提供）：McsSa基因座的乳腺癌耐药修饰物已定位于大鼠5号染色体上约11.0 Kb的区域。McsSa被证明是一个复合基因座，由合成相互作用的两个组分亚基因座Mcs5a1（32 Kb）和Mcs5a2（84 Kb）组成。看来，在这两个亚基因座的致病元件是不可能的蛋白质编码基因。人类基因组中与Mcs5a2正交的区域已经在两个大型病例对照研究（n =约12，000名妇女）中测试了与乳腺癌风险的相关性。发现与该区域中的SNP（SNP-3）高度显著的关联。与SNP-3相关的SNP的位置将Mcs5a2区域减少到约20 Kb。当前项目的目标是确定和表征这些基因座内改变乳腺癌风险的基因组元件，并扩展我们的人类关联研究。目的包括使用同类大鼠探索问题，如是否Mcs5a1和-5a2相互作用的顺式和反式，以及它们是否在乳腺细胞自主的方式行事。此外，将评价Mcs5a抑制卵巢非应答性乳腺癌的能力。将从遗传学角度剖析Mcs56处显性抗性等位基因与显性易感性增加等位基因之间的上位性相互作用。比较基因组学与使用多种抗体的ChIP-on-CHIP实验一起将用于鉴定另外的转录和非转录的潜在McsSa候选物。将表征潜在候选物在乳腺癌敏感性和抗性大鼠品系以及人敏感性和抗性等位基因之间的差异。有分歧的人将被提升为候选人。将使用BAG转基因或敲除模型在体内评价选择性候选物。人类研究将评估McsSal中SNP标记的等位基因与乳腺癌风险的关联。流行病学研究也将扩展到确定与乳腺癌风险相关的SNP是否也与DCIS（一种癌前乳腺病变）的风险相关。这些研究将继续提供一个更好的了解复杂的遗传学基础遗传风险的乳腺癌。识别和表征导致人类和大鼠乳腺癌耐药性的McsSa中的致病基因组元件可能为乳腺癌的病因学提供独特的见解。最后，生成的数据可能会提供乳腺癌风险的临床标志物和化学预防的新靶点。

DESCRIPTION (provided by applicant): A mammary cancer resistance modifier at the McsSa locus has been localized to an approximate 11.0 Kb region on rat chromosome 5. McsSa was shown to be a compound locus consisting of two component sub-loci Mcs5a1 (32 Kb) and Mcs5a2 (84 Kb) that synthetically interact. It appears that the causative element at both sub-loci is unlikely to be a protein coding gene. Regions of the human genome orthologous to Mcs5a2 have been tested for association with breast cancer risk in two large case-control studies (n = approximately 12,000 women). A highly significant association with an SNP (SNP-3) in this region was found. The location of SNPs that are correlated to SNP-3 reduces the Mcs5a2 region to approximately 20 Kb. The goal of the current project is to identify and characterize the genomic element(s) within these loci that modify breast cancer risk and to extend our human association studies. Aims include using congenic rats to explore questions as whether Mcs5a1 and -5a2 interact in cis and trans and whether they act in a mammary cell-autonomous manner. In addition, the ability of Mcs5a to inhibit hormonally non-responsive mammary cancer will be evaluated. The epistatic interaction between the dominant resistance allele at McsSa over the dominant increased susceptibility allele at Mcs56 will be genetically dissected. Comparative genomics together with ChlP-on-CHIP experiments using multiple antibodies will be used to identify additional transcribed and non-transcribed potential McsSa candidates. Potential candidates will be characterized for differences between mammary cancer sensitive and resistant rat lines as well as human sensitive and resistant alleles. Those with differences will be elevated to candidate status. Selective candidates will be evaluated in vivo using BAG transgenic or knockout models. Human studies will evaluate SNP-marked alleles in McsSal for association with breast cancer risk. Epidemiologic studies will also be extended to determine if the SNP(s) that associates with breast cancer risk also associates with the risk for DCIS, a premalignant breast lesion. These studies will continue to provide a better understanding to the complex genetics underlying inherited risk to breast cancer. Identifying and characterizing the causative genomic elements in McsSa that lead to breast cancer resistance in humans and rats may provide unique insights into the etiology of breast cancer. Finally, the data to be generated may provide clinical markers of breast cancer risk and novel targets for chemoprevention.