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（来自申请人的逐字描述）：佩吉特骨病是指 仅次于骨质疏松症的第二大常见骨代谢疾病。它导致 快速骨形成，改变骨骼的强度和形状。 佩吉特病的易感性在一些家庭中与以下因素有关： 18号染色体q。然而，最近的证据表明， 佩吉特氏病是遗传异质性的，并且两个或更多个基因座必须 与家族性佩吉特病易感性有关骨肉瘤是一种罕见的 佩吉特病的严重并发症。我们的实验室发现了一种 佩吉特病和骨肉瘤之间的关系。分析两种散发性 佩吉特病患者的骨肉瘤和骨肉瘤显示， 这些肿瘤经历了肿瘤特异性的结构杂合性丢失 (LoH)在一个与佩吉特病易感性紧密相关的区域。 这表明，一些参与肿瘤发生的基因， 骨肉瘤也可能与佩吉特病的易感性有关。那里 这是该提案的三个目标。第一个是识别额外的基因 容易患上佩吉特病我们建议利用我们独特的 收集pagetic骨肉瘤，以等位基因型正常， pagetic骨肉瘤患者的pagetoid骨和肿瘤样本， 鉴定可能含有新的肿瘤抑制基因座的区域， pagetic或tumongenic过程。然后可以对这些候选区域进行测试 在染色体18 q-非连锁佩吉特中与家族性佩吉特病连锁 以确定这些新的肿瘤抑制基因中的任何一个是否可以 代表额外的佩吉特易感基因座。我们可能会 用这种方法找不到与佩吉特病易感性有关的基因。在 在这种最坏的情况下，我们仍然会实现第二个目标， 描述发生在pagetic骨肉瘤的遗传事件， 将其与散发性骨肉瘤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有共同的遗传基因， 起源.此外，通过在我们的分析中包括pagetoid骨，我们将能够 实现我们的第三个目标，即确定是否有基因起作用， 在散发性佩吉特病的发病中以肿瘤抑制剂样的方式。 总之，这些分析将使我们能够检查两种倾向， 家族性佩吉特病，以及表征的分子遗传学 佩吉特骨肉瘤和散发性佩吉特病。