Characterizing a Breast Cancer Modifier Locus That Associates with Human Risk

描述(申请人提供)：McsSa基因座上的一个乳腺癌耐药修饰基因已定位在大鼠5号染色体上约11.0kb的区域。McsSa被证明是一个由两个组成的亚基因座组成的复合基因座，Mcs5a1(32kb)和Mcs5a2(84kb)综合作用。这两个亚位点上的致病因素似乎都不太可能是蛋白质编码基因。人类基因组中与Mcs5a2同源的区域已经在两个大型病例对照研究(n=大约12,000名妇女)中被测试与乳腺癌风险有关。在该地区发现了与SNP(SNP-3)高度相关的基因。与SNP-3相关的SNP的位置使Mcs5a2区域减少到约20kb。目前项目的目标是识别和表征这些基因座中改变乳腺癌风险的基因组元素(S)，并扩大我们的人类关联研究。目的包括利用同基因大鼠探索Mcs5a1和-5a2是否在顺式和反式中相互作用，以及它们是否以乳腺细胞自主的方式发挥作用。此外，还将评估Mcs5a抑制激素反应不敏感的乳腺癌的能力。对McsSa的显性抗性等位基因与Mcs56的显性感病等位基因之间的上位性交互作用进行了遗传解剖。比较基因组学和使用多种抗体的ChlP芯片实验将被用来识别更多的转录和非转录的潜在McsSa候选者。潜在的候选基因将被描述为乳腺癌敏感和耐药大鼠品系以及人类敏感和耐药等位基因之间的差异。那些有分歧的人将被提升为候选人。选定的候选者将使用BAG转基因或基因敲除模型在体内进行评估。人类研究将评估McsSal中SNP标记的等位基因与乳腺癌风险的相关性。流行病学研究也将扩大，以确定与乳腺癌风险相关的单核苷酸多态(S)是否也与乳癌前病变DCIS的风险相关。这些研究将继续为乳腺癌遗传风险背后的复杂遗传学提供更好的理解。识别和鉴定McsSa中导致人类和大鼠乳腺癌耐药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，将产生的数据可能提供乳腺癌风险的临床标记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.