CLONING NOVEL GENES FOR PAGETS DISEASE AND OSTEOSARCOMA

描述(改编自申请者摘要)：帕吉特氏病 骨骼，或变形骨炎，是一种以快速骨质为特征的骨骼疾病。 重塑，导致异常的骨形成。它是第二大 骨质疏松后常见的代谢性骨病，影响3%-4%的受试者 年龄在40岁以上。Paget病的原因尚不清楚，但 最近，两条证据汇聚在一起，表明佩吉特的 疾病的易感性可能有遗传因素。第一，联动 多代Paget病家系分析显示与 染色体18q中靠近D18S42多态位点处的区域。这 次区域也被确定为 家族性扩张性骨溶解(FEO)，一种类似Paget病的遗传性疾病 疾病。其次，Paget病最严重的并发症之一 是骨肉瘤发病率的显著增加。大致 1-5%的Paget患者发展为骨肉瘤，这意味着增加 风险是普通人群的几千倍，而且是 40岁以后相当一部分骨肉瘤的潜在基础 几年前。肿瘤特异性结构杂合性缺失(LOH) 申请实验室对骨肉瘤的分析发现 可能的肿瘤抑制基因，映射到染色体的同一亚区 18q与家族性Paget‘s和FEO相关。这个协会 Paget病和骨肉瘤之间的关系表明 途径，或两个密切相关的基因。这背后的假设是 IRPG是骨肉瘤肿瘤发生、家族史之间的联系 Paget病和FEO是由一个或几个基因的存在引起的 位于染色体18q这一区域的紧密相关基因。为了测试这一点 假设，候选基因将从定义的区域内分离出来 家族性Paget病家系和LOH最小区域 在骨肉瘤中，这些候选基因将被检测为证据 其中一个或多个与Paget病的易感性有关 和/或骨肉瘤。

DESCRIPTION (Adapted from the Applicant's Abstract): Paget's disease of bone, or osteitis deformans, is a bone disorder characterized by rapid bone remodeling, resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3-4% of subjects over the age of 40. The causes of Paget's disease are unknown but, recently, two lines of evidence have converged to suggest that Paget's disease may have a genetic component to its predisposition. First, linkage analysis of families with multigenerational Paget's disease show linkage to a region of chromosome 18q near to the polymorphic locus D18S42. This subregion has also been identified as the location for the locus for Familial Expansile Osteolysis (FEO), a hereditary disease similar to Paget's disease. Secondly, one of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1-5% of Paget's patients develop osteosarcoma, which represents an increase of risk that is several thousand-fold over the general population, and is the underlying basis for a significant fraction of osteosarcoma after 40 years of age. Tumor-specific loss of constitutional heterozygosity (LoH) analysis of osteosarcomas by the applicant laboratory has identified a putative tumor suppressor gene that maps to the same subregion of chromosome 18q that was linked to both familial Paget's and FEO. This association between Paget's disease and osteosarcoma suggests either a common genetic pathway, or two closely associated genes. The underlying hypothesis of this IRPG is that the association between osteosarcoma tumorigenesis, familial Paget's disease and FEO is due to the presence of either a gene, or several closely associated genes in this region of chromosome 18q. To test this hypothesis, candidate genes will be isolated from within the region defined by both the familial Paget's disease families and the minimal region of LoH in osteosarcomas, and these candidate genes will be tested for evidence that one or more of them is responsible for predisposition to Paget's disease and/or osteosarcoma.