Locating Novel Paget's Loci by Tumor Allelotyping

通过肿瘤等位基因定位Novel Paget的基因座

• 批准号: 6632777
• 负责人: MARC F HANSEN
• 金额: $ 28.78万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6632777
• 关键词: alleles; biotechnology; chromosome disorders; clinical research; family genetics; fluorescent in situ hybridization; gel electrophoresis; gene expression; genetic markers; genetic screening; genetic susceptibility; genotype; human genetic material tag; human subject; linkage mapping; loss of heterozygosity; microarray technology; northern blottings; nucleic acid hybridization; osteitis deformans; osteosarcoma; polymerase chain reaction; tumor suppressor genes

DESCRIPTION (Verbatim from the Applicant): Paget's Disease of bone is the second most common metabolic disease of bone after osteoporosis. It results in rapid bone formation, altering the strength and shape of the bone. Predisposition to Paget's Disease has been linked in some families to chromosome 1 8q. However, recent evidence has shown that predisposition to Paget's Disease is genetically heterogeneous and that two or more loci must be involved in familial Paget's Disease predisposition. Osteosarcoma is a rare but serious complication of Paget's Disease. Our laboratory has identified an association between Paget's Disease and osteosarcoma. Analysis of both sporadic osteosarcomas and osteosarcomas from patients with Paget's Disease revealed that these tumors undergo tumor-specific loss of constitutional heterozygosity (LoH) in a region that is tightly linked to predisposition to Paget's Disease. This suggests that some of the genes that are involved in tumongenesis of osteosarcomas may also be involved in predisposition to Paget's Disease. There are three goals for this proposal. The first is to identify additional genes that predispose to Paget's Disease. We propose to take advantage of our unique collection of pagetic osteosarcomas to allelotype the entire genomes of normal, pagetoid bone, and tumor samples from patients with pagetic osteosarcoma to identify regions that may harbor novel tumor suppressor loci involved in either the pagetic or tumongenic process. These candidate regions can then be tested for linkage to familial Paget's Disease in chromosome 18q-unlinked Paget's families to determine if any of these novel tumor suppressor genes may represent additional Paget's predisposition loci. It is possible that we will not find genes involved in predisposition to Paget's Disease by this method. In this worst-case scenario, we will still realize our second goal, which is to characterize the genetic events that take place in pagetic osteosarcoma and to compare them to the genetic events that take place in sporadic osteosarcoma. This will allow us to determine whether these two diseases share common genetic origins. Further, by including pagetoid bone in our analysis we will be able to realize our third goal, which is to determine whether there are genes which act in a tumor suppressor-like fashion in the onset of sporadic Paget's Disease. Together, these analyses will allow us to examine both the predisposition to familial Paget's Disease, as well as to characterize the molecular genetics of pagetic osteosarcoma and sporadic Paget's Disease.

描述（申请人的逐字病）：Paget的骨骼疾病是 骨质疏松症的第二大最常见的骨骼代谢疾病。它导致 快速骨形成，改变骨骼的强度和形状。 佩吉特氏病的易感性已与某些家庭联系在一起 染色体1 8Q。但是，最近的证据表明 paget病在遗传上是异质的，两个或多个基因座必须是 参与家族性paget病的易感性。骨肉瘤是罕见的，但 paget病的严重并发症。我们的实验室已经确定了 paget病与骨肉瘤之间的关联。两种零星的分析 paget病患者的骨肉瘤和骨肉瘤显示 这些肿瘤会经历宪法杂合性的肿瘤特异性丧失 （LOH）在与Paget疾病易感性紧密相关的区域中。 这表明某些与肿瘤发生的基因 骨肉瘤也可能参与paget病的易感性。那里 是该提议的三个目标。首先是识别其他基因 这种易于paget病。我们建议利用我们的独特 雌性骨肉瘤的收集到正常的整个基因组的化合物 Pagetoid骨骼和来自pagetic骨肉瘤患者的肿瘤样品 识别可能含有新型肿瘤基因座的区域 子宫或肿瘤过程。然后可以测试这些候选区域 在染色体18q无联系的paget的染色体中与家族性paget病的联系 家庭以确定这些新型肿瘤抑制基因是否可以 代表其他Paget的倾向基因座。我们可能会 通过这种方法，找不到与Paget疾病易感的基因。在 在最糟糕的情况下，我们仍然会意识到我们的第二个目标，即 表征在pagetic骨肉瘤中发生的遗传事件和 将它们与零星骨肉瘤发生的遗传事件进行比较。 这将使我们能够确定这两种疾病是否共享常见的遗传 起源。此外，通过在我们的分析中包括pagetoid骨头，我们将能够 意识到我们的第三个目标，即确定是否有一些基因 在零星paget病的发作中，以肿瘤抑制剂方式。 这些分析一起将使我们能够检查 家族性paget病，以及表征的分子遗传学 pagetic骨肉瘤和零星paget病。