GENETIC EPIDEMIOLOGY OF CHILDHOOD SARCOMA

我们之前在儿童和青少年肉瘤患者中证明了一个主要基因易患癌症的统计证据。我们有证据表明，不同亲属、不同世代和选择的先证者特征的风险存在异质性。癌症的家族性模式随着时间的推移而演变，经过20多年的观察，越来越多的证据表明一个主要基因。到目前为止，已经发现一些种类的肿瘤抑制基因p53有生殖系突变，这为主要基因的存在提供了强有力的证据。然而，在一些临床相似的种类中，p53可以被排除为癌症易感位点。我们描述了p53突变状态、突变类型、性别、癌症部位、吸烟状况、世代和年龄的风险；令人惊讶的是，除了突变类型外，所有这些因素的风险都存在异质性，截断突变赋予的风险与错义突变相似。世代（或出生年份，因为它们是混淆的）是p53突变类型和非p53癌症易感性类型风险的主要决定因素。我们现在建议使用分离分析的回归模型来描述风险的异质性，并增加观察的关键年份。该策略将是确定肉瘤种类中残留的癌症风险，并确定其他主要基因或修饰基因。当前的目标是(1)在p53突变种类中，确定生殖系p53突变对观察到的家族性癌症聚集的影响程度，进一步表征表型，并确定风险的额外变化；(2)在非p53易感癌症种类中，确定其他主要的癌症易感基因，表征表型和风险修饰因子，并确定产生表型的遗传途径。该项目的研究结果将为儿童肉瘤和相关肿瘤的遗传病因提供信息，为遗传咨询提供信息，并为研究修饰位点在家族性癌症聚集中的作用提供资源。

We previously demonstrated statistical evidence for a major gene predisposing to cancer in kindreds of childhood and adolescent sarcoma patients. We had evidence for heterogeneity in risk by kindred, by generation, and by selected proband characteristics. The familial pattern of cancer evolved over time, with increasing evidence for a major gene after more than 20 years of observation. To date, some of the kindreds that provide strong evidence for a major gene have been found to have germline mutations in the tumor suppressor gene, p53. However, p53 can be ruled out as the cancer susceptibility locus in some clinically similar kindreds. We have characterized the risk in p53 mutation status, mutation type, sex, cancer site, smoking status, generation and age; surprisingly, there is heterogeneity in risk for all those factors except the mutation type, with truncating mutations conferring risks similar to those of missense mutations. Generation (or birth year, as they are confounded) is a major determinant of risk both in p53 mutation kindreds and non p53 cancer prone kindreds. We now propose to characterize the heterogeneity in risk using a strategy orf regressive models of segregation analysis, with additional critical years of observation. The strategy will be to identify residual cancer risk in the sarcoma kindreds, and to identify other major genes or modifying genes. The immediate goals are (1) in the p53 mutation kindreds, to identify the extent to which germline p53 mutations account for the observed familial cancer aggregation, to characterize further the phenotype, and to identify additional variation in risk, and (2) in the non p53 cancer prone kindreds, to identify the other major cancer susceptibility gene(s), to characterize the phenotype(s) and risk modifiers, and to define the genetic pathways that give rise to the phenotype(s). Findings from this project should provide information regarding the genetic etiology of childhood sarcomas and associated tumors, information for genetic counseling, and a resource from which to investigate the role of modifier loci in familial cancer aggregates.