GENETIC EPIDEMIOLOGY OF CHILDHOOD SARCOMA

我们已经证明了一个主要基因的统计证据，在运动的 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有力证据的激酶， 被发现在肿瘤抑制基因p53中有生殖细胞突变。 然而，统计结果表明，一个主基因可能并不起作用， 对于所有的癌症风险的变化，观察内或之间的kinematic。 例如，先证者的兄弟姐妹患儿童癌症的风险更大 比父母的兄弟姐妹;观察到亲属的额外风险， 胚胎性横纹肌肉瘤患者的家庭与其他 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了一个主基因外， 金斯。因此，我们建议确定p53的贡献 生殖系突变对整体癌症风险的影响， 连锁和分离分析。 首先，我们将测试 与p53的特异性连接。 然而，如果调查结果支持参与 我们提出的策略可以推广到其他遗传位点， 来鉴定其他的主基因或修饰基因。 近期目标 仍然需要确定生殖系p53突变在多大程度上可以解释 在肉瘤组群中观察到的家族性癌症聚集。 与 这种方法可以描述年龄，性别和部位特异性 p53种系突变的突变率，表型复制的程度， kinetics，并可以识别任何变化的风险不归因于p53 作为一个主要的基因。 此外，我们还将确定从头开始的频率 p53突变，以及p53种系突变对 第二种恶性肿瘤的表型。本项目的结果 应提供足够的信息，以制定遗传 儿童肉瘤患者的检测，遗传咨询指南 关于p53生殖系突变的影响，以及一个框架， 由此来研究其他遗传位点在家族性疾病中的作用。 癌症聚集。

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.