GENETIC EPIDEMIOLOGY OF CHILDHOOD SARCOMA

我们已经证明了一个主要基因在家族性心脏病中的统计证据。 儿童和青少年软组织和骨肉瘤患者。到目前为止， 其中一些为主基因提供了强有力证据的类型 被发现在肿瘤抑制基因P53中有胚系突变。 然而，统计结果表明，一个主基因可能不能解释 对于在家庭内部或家庭之间观察到的癌症风险的所有差异。 例如，先证者的兄弟姐妹患儿童期癌症的风险更大 比父母的兄弟姐妹更危险；对亲属的额外风险在 胚胎性横纹肌肉瘤患者家族与其他患者的比较 组织学软组织肉瘤类型：一个重要的多因素 在骨肉瘤中观察到除一个主要基因外的贡献 一家亲。因此，我们建议确定P53的贡献 使用联合策略将生殖系突变与总体癌症风险 连锁分析和分离分析。最初，我们将测试 与P53特异性连锁。然而，如果调查结果支持参与 对于其他遗传基因座，我们提出的策略可以推广。 以确定其他主效基因或修饰基因。眼前的目标 仍需确定胚系p53突变能在多大程度上解释 在肉瘤队列中观察到的家族性癌症聚集。使用 这种方法我们可以表征特定于年龄、性别和地点的 P53胚系突变的外显率，表型突变的程度 ，并可以识别任何不是由p53引起的风险变异 作为一个主要基因。此外，我们将确定从头开始的频率 P53基因突变，以及P53胚系突变对 第二种恶性肿瘤的表型。此项目的发现 应该提供足够的信息来制定遗传基因的指南 儿童肉瘤患者检测，遗传咨询指南 关于p53胚系突变的含义，以及一个框架 从中研究其他基因座在家族性遗传病中的作用 癌症聚集物。

We have demonstrated statistical evidence for a major gene in kindreds of childhood and adolescent soft tissue and bone sarcoma patients. To date, some of these kindreds that provide strong evidence for a major gene have been, found to have germline mutations in the tumor suppressor gene, p53. Statistical findings, however, suggest that a major gene may not account for all of the variation in cancer risk observed within or among kindreds. For example, siblings of probands are at greater risk of childhood cancer than siblings of parents; additional risk to relatives was observed in families of patients with embryonal rhabdomyosarcoma as compared to other histologic soft tissue sarcoma types; a significant multifactorial contribution in addition to a major gene was observed in the bone sarcoma kindreds. We therefore propose to determine the contribution of p53 germline mutations to the overall cancer risk using a strategy of combined linkage and segregation analysis. Initially we will be testing for linkage to p53 specifically. However, if the findings support involvement of other genetic loci, the strategy we have proposed could be generalized to identify other major genes or modifying genes. The immediate goals remain to identify the extent to which germline p53 mutations can account for the observed familial cancer aggregation in the sarcoma cohort. With this approach we can characterize the age-, sex- and site- specific penetrance for p53 germline mutations, the extent of phenocopies in the kindreds, and can identify any variation in risk not attributable to p53 as a major gene. In addition, we will determine the frequency of de novo mutations in p53, and the contribution of p53 germline mutations to the phenotype of a second malignant neoplasm. Findings from this project should provide sufficient information to develop guidelines for genetic testing of childhood sarcoma patients, guidelines for genetic counseling regarding the implications of a p53 germline mutation, and a framework from which to investigate the role of other genetic loci in familial cancer aggregates.