GENETIC EPIDEMIOLOGY OF CHILDHOOD SARCOMA

我们先前在儿童和青少年肉瘤患者的家族中展示了一个易患癌症的主要基因的统计证据。我们有证据表明，根据亲属、世代和选定的先证者特征，风险存在异质性。癌症的家族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存在一个主要基因。到目前为止，一些为主基因提供强有力证据的家族已经被发现在肿瘤抑制基因P53中存在胚系突变。然而，在一些临床相似的家族中，可以排除P53作为癌症易感基因的可能性。我们已经表征了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，除突变类型外，所有这些因素的风险都存在异质性，截断突变带来的风险与错义突变相似。在P53突变家族和非P53癌症易感家族中，世代(或出生年份，因为他们被混淆了)是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的策略来表征风险的异质性，并加上额外的关键观察年数。该策略将确定肉瘤家族中残留的癌症风险，并确定其他主要基因或修饰基因。近期的目标是(1)在P53突变家系中，确定胚系P53突变在所观察到的家族性癌症聚集中的作用程度，进一步表征表型，并确定风险的其他变异，以及(2)在非P53癌易感家系中，确定另一个主要的癌症易感基因(S)，鉴定表型(S)和风险修饰因素，并确定导致表型的遗传途径(S)。这个项目的发现应该提供有关儿童肉瘤和相关肿瘤的遗传病因的信息，遗传咨询的信息，以及研究修饰基因在家族性癌症聚集性中的作用的资源。

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.