GENETIC EPIDEMIOLOGY OF CHILDHOOD SARCOMA

儿童肉瘤的遗传流行病学

• 批准号: 6198227
• 负责人: LOUISE C STRONG
• 金额: $ 13.54万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-23 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6198227
• 关键词: cancer risk; clinical research; family genetics; gene frequency; gene mutation; genetic susceptibility; human subject; neoplasm /cancer epidemiology; neoplasm /cancer genetics; p53 gene /protein; pediatric neoplasm /cancer; sarcoma

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.

我们先前证明了在儿童期和青少年肉瘤患者中易于癌症的主要基因的统计证据。我们有证据表明，按亲属，一代和选定的概率特征划分的风险异质性。癌症的家族模式随着时间的流逝而发展，经过20多年的观察，越来越多的主要基因的证据。迄今为止，已经发现一些为主要基因提供有力证据的亲属在肿瘤抑制基因中具有生殖线突变，p53。但是，在某些临床上类似的同类产品中，可以将p53排除为癌症易感性基因座。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，发电和年龄的风险；令人惊讶的是，除突变类型外，所有这些因素的风险存在异质性，截断突变的风险与错义突变相似。一代（或出生年，因为它们被混淆）是p53突变和非p53癌症的主要决定因素。现在，我们建议使用策略ORF回归分离分析模型来表征风险中的异质性，并具有更多关键的观察年份。该策略将是识别肉瘤亲属中残留的癌症风险，并确定其他主要基因或修饰基因。直接的目标是（1）在p53突变中，以确定种系p53突变的程度解释了观察到的家族性癌症的聚集，以进一步表征表型，并确定风险的额外变化，（2）在非p53癌症中，易于识别其他主要的癌症敏感性（S），以识别其他主要的癌症疾病（S），以识别出（S），并构成了遗传（S）（S）（S）（S）。产生表型的途径。该项目的发现应提供有关儿童肉瘤和相关肿瘤的遗传病因，遗传咨询信息的信息，以及研究修饰基因座基因座在家族性癌症骨料中的作用的资源。