Characterizing a Breast Cancer Modifier Locus That Associates with Human Risk

表征与人类风险相关的乳腺癌修饰基因座

• 批准号: 7408637
• 负责人: MICHAEL N GOULD
• 金额: $ 39.56万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-13 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7408637
• 关键词: Affect; Alleles; Antibodies; Area; Biological Assay; Case-Control Studies; Cells; Chemoprevention; Chromosomes; Chromosomes, Human, Pair 5; Clinical Markers; Code; Complex; DNA Repair; Data; Data Analyses; Disease; Duct (organ) structure; Elements; Enhancers; Epidemiologic Studies; Estrogen Metabolism; Etiology; Evaluation; Frequencies; Genes; Genetic; Genetic Polymorphism; Genetic Risk; Genome; Genomics; Goals; Human; Human Genetics; Human Genome; Indium; Inherited; Investigation; Knock-out; Laboratories; Lead; Localized; Location; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Maps; Minor; Modeling; Noninfiltrating Intraductal Carcinoma; Parents; Penetrance; Phenotype; Population; Predisposition; Premalignant; Proteins; Quantitative Trait Loci; RNA Splicing; Rattus; Recombinants; Resistance; Retroviral Vector; Risk; Role; Series; Site; Testing; Transgenic Organisms; Transplantation; Wisconsin; Woman; base; breast lesion; cancer risk; case control; chromatin immunoprecipitation; comparative; congenic; disorder risk; genetic element; human population study; human study; in vivo; insight; malignant breast neoplasm; novel; prevent; ras Oncogene; research study; size; vector

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.

描述（申请人提供）：McsSa 基因座上的乳腺癌抗性修饰剂已定位于大鼠 5 号染色体上大约 11.0 Kb 的区域。McsSa 被证明是一个复合基因座，由两个合成相互作用的亚基因座 Mcs5a1 (32 Kb) 和 Mcs5a2 (84 Kb) 组成。看来两个亚基因座的致病元件不太可能是蛋白质编码基因。在两项大型病例对照研究（n = 约 12,000 名女性）中，已经测试了与 Mcs5a2 同源的人类基因组区域与乳腺癌风险的关联。发现与该区域的 SNP (SNP-3) 存在高度显着的关联。与 SNP-3 相关的 SNP 位置将 Mcs5a2 区域缩小至约 20 Kb。当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件，并扩展我们的人类关联研究。目的包括使用同类大鼠来探索 Mcs5a1 和 -5a2 是否以顺式和反式相互作用以及它们是否以乳腺细胞自主方式起作用等问题。此外，还将评估 Mcs5a 抑制激素无反应性乳腺癌的能力。 McsSa 的显性抗性等位基因与 Mcs56 的显性易感性增加等位基因之间的上位相互作用将被进行基因剖析。比较基因组学以及使用多种抗体的 ChlP-on-CHIP 实验将用于识别其他转录和非转录的潜在 McsSa 候选者。潜在候选者将针对乳腺癌敏感和耐药大鼠系以及人类敏感和耐药等位基因之间的差异进行表征。那些有分歧的人将被提升为候选人。将使用 BAG 转基因或敲除模型对选定的候选者进行体内评估。人类研究将评估 McsSal 中 SNP 标记的等位基因与乳腺癌风险的关联。流行病学研究也将扩大，以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。这些研究将继续帮助人们更好地了解乳腺癌遗传风险背后的复杂遗传学。鉴定和表征 McsSa 中导致人类和大鼠乳腺癌抵抗的致病基因组元件可能会为乳腺癌的病因学提供独特的见解。最后，生成的数据可以提供乳腺癌风险的临床标志物和化学预防的新靶标。