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: 6324240
• 负责人: MARC F HANSEN
• 金额: $ 28.14万
• 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/6324240
• 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（申请人逐字记录）：佩吉特骨病是 仅次于骨质疏松症的第二常见骨代谢疾病。结果是 快速骨形成，改变骨骼的强度和形状。 在某些家庭中，佩吉特病的易感性与 1号染色体8q。然而，最近的证据表明，倾向 佩吉特氏病具有遗传异质性，两个或多个基因座必须是 涉及家族佩吉特氏病易感性。骨肉瘤是一种罕见但 佩吉特病的严重并发症。我们的实验室已经确定了一个 佩吉特氏病与骨肉瘤之间的关联。分析两种零星 骨肉瘤和佩吉特氏病患者的骨肉瘤被发现 这些肿瘤经历肿瘤特异性的组成性杂合性丧失 (LoH) 所在区域与佩吉特氏病的易感性密切相关。 这表明一些与肿瘤发生有关的基因 骨肉瘤也可能与佩吉特氏病的易感性有关。那里 这是该提案的三个目标。首先是识别额外的基因 容易患佩吉特氏病。我们建议利用我们独特的优势 收集页面骨肉瘤以对正常人的整个基因组进行等位基因分型， 佩吉特骨和来自佩吉特骨肉瘤患者的肿瘤样本 识别可能含有涉及任一新肿瘤抑制基因座的区域 页面或致瘤过程。然后可以测试这些候选区域 18q 染色体非连锁佩吉特氏病与家族性佩吉特氏病的关联 家族以确定这些新的肿瘤抑制基因是否可能 代表额外的佩吉特易感位点。我们有可能会 通过这种方法没有发现与佩吉特氏病易感性相关的基因。在 在这种最坏的情况下，我们仍然会实现我们的第二个目标，那就是 描述页面骨肉瘤中发生的遗传事件的特征并 将它们与散发性骨肉瘤中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具有共同的遗传基因 起源。此外，通过在我们的分析中包含 pagetoid 骨骼，我们将能够 实现我们的第三个目标，即确定是否有基因发挥作用 在散发性佩吉特病的发作中以类似肿瘤抑制的方式。 总之，这些分析将使我们能够检查以下两种倾向： 家族性佩吉特氏病，以及表征其分子遗传学 佩吉特骨肉瘤和散发性佩吉特病。