CLONING NOVEL GENES FOR PAGETS DISEASE AND OSTEOSARCOMA

描述（改编自申请人的摘要）： 骨炎或变形性骨炎是一种以快速骨形成为特征的骨疾病， 重塑，导致骨形成异常。 它是第二大 骨质疏松症后常见的代谢性骨病，影响3-4%的受试者 超过40岁 佩吉特病的病因尚不清楚， 最近，两种证据表明，佩吉特的 疾病的易感性可能有遗传因素。 一、联动 对多代佩吉特病家族的分析显示， 18号染色体上靠近多态位点D18 S42的区域。 这 该次区域也被确定为 家族性膨胀性骨溶解症（FEO），一种类似于佩吉特的遗传性疾病 疾病 其次，佩吉特病最严重的并发症之一 是骨肉瘤发病率的显著增加。 约 1-5%的佩吉特患者发生骨肉瘤， 风险是普通人群的几千倍， 40岁以后骨肉瘤的显著比例的潜在基础 岁的 肿瘤特异性组成型杂合性缺失（洛） 申请人实验室对骨肉瘤的分析发现， 定位于染色体相同亚区的假定肿瘤抑制基因 18 q与家族性佩吉特和FEO都有关联。 这种关联 佩吉特病和骨肉瘤之间的联系表明 基因或两个紧密相关的基因。 这背后的假设是 IRPG是骨肉瘤肿瘤发生、家族性 佩吉特病和FEO是由于一个或多个基因的存在， 在染色体18 q的这个区域中紧密相关的基因。 为了验证这一 假设，候选基因将从定义的区域内分离 家族性佩吉特病家系和洛最小区域 在骨肉瘤中，这些候选基因将被测试，以证明 其中一个或多个与佩吉特病的易感性有关 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.