Genetic Epidemiology of Familial Childhood Cancer

家族性儿童癌症的遗传流行病学

• 批准号: 7118384
• 负责人: LOUISE C STRONG
• 金额: $ 15.6万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7118384
• 关键词: Li Fraumeni syndrome; Wilms' tumor; biotechnology; cancer risk; family genetics; gene environment interaction; gene mutation; genetic models; genetic screening; genetic susceptibility; human genetic material tag; human subject; linkage mapping; mathematical model; neoplasm /cancer genetics; p53 gene /protein; pediatric neoplasm /cancer; sarcoma

The goal of this ongoing project is to identify and characterize the genes that contribute to cancer risk in familial childhood cancer syndromes of sarcoma (Li Fraumeni Syndrome, LFS) and (new addition to this project) Wilms' tumor (WT). For each syndrome we have demonstrated known genes that contribute (p53 and WT1), evidence for additional genetic contribution, and evidence for genetic heterogeneity. In families with germline p53 mutations we find evidence for significant heterogeneity in risk by gender and generation, with a younger age of onset in successive generations. We have examples of both syndromes in which we have ruled out p53 or WT1 as the susceptibility locus, and have identified new regions of the genome that may contribute. To identify other cancer susceptibility genes and risk modifiers, we propose to use data generated by continued longitudinal study and from the other projects and cores to perform combined genetic linkage and segregation analysis in the familial childhood cancer syndromes. The proposal includes using regressive logistic models, Monte Carlo Markov Chain methods, Kaplan Meier and proportional hazards survival analyses. We will incorporate measures of telomere function as they relate to cancer risk or to a given genotype. The specific aims are (1) to use linkage and segregation analysis to identify additional risk modifiers in the p53 mutation LFS kindreds, including mechanisms to account for the observed generation effect and factors associated with multiple primary tumors, and to characterize the phenotype and genotype of the non-p53 cancer prone (LFS) kindreds, (2) to identify the role of genetic and treatment related risk factors in the outcome of multiple additional neoplasms in the sarcoma cohorts, and (3) to identify the genetic model(s) that best characterize familial Wilms' tumor and provide a guide for identification of the relevant genetic pathways in Wilms tumor. These analyses provide feedback to the projects regarding the contribution of newly identified genomic regions or genes. The importance of cancer genetic susceptibility and second primary cancers, using rare syndromes as models, was recognized by an NCI survivorship conference on that topic in 2004. This P01 has the unique combination of human and mouse genetics to identify new genes and genetic mechanisms of cancer susceptibility that will be significant for populations as well as the rare genetic syndromes.

这个正在进行的项目的目标是确定和描述基因，有助于癌症的风险， 肉瘤的家族性儿童癌症综合征（Li Fraumeni综合征，LFS）和（新增加的 Wilms' tumor（WT）。对于每种综合征，我们已经证明了已知的基因，有助于（p53 和WT 1），额外的遗传贡献的证据，和遗传异质性的证据。在家庭中 对于生殖系p53突变，我们发现了性别和世代风险显著异质性的证据， 在连续的几代中发病年龄更小。我们有这两种综合征的例子， 已经排除了p53或WT1作为易感基因座，并确定了基因组的新区域， 可以贡献。为了确定其他癌症易感基因和风险修饰因子，我们建议使用数据 通过持续的纵向研究以及其他项目和核心组合来执行 家族性儿童癌症综合征的遗传连锁和分离分析这项提议包括 使用回归Logistic模型、Monte Carlo Markov Chain方法、Kaplan Meier和比例 危险生存分析。我们将纳入端粒功能的措施，因为它们与癌症风险或 to a given给定genotype基因型.具体目的是：（1）利用连锁和分离分析， p53突变LFS激酶中的风险修饰因子，包括解释观察到的 与多种原发性肿瘤相关的遗传效应和因素，并表征表型和 基因型的非p53癌症倾向（LFS）激酶，（2）以确定遗传和治疗相关的作用 肉瘤队列中多种额外肿瘤结局的风险因素，以及（3）确定 最好地表征家族性肾母细胞瘤的遗传模型，并为鉴别 Wilms肿瘤相关的遗传通路。这些分析为项目提供了关于 新鉴定的基因组区域或基因的贡献。 癌症遗传易感性和第二原发性癌症的重要性，使用罕见综合征作为 2004年，国家癌症研究所关于这一主题的生存会议承认了这一模式。这款P01具有独特的 人类和小鼠遗传学的结合，以确定新的基因和癌症的遗传机制 易感性，这将是显着的人口以及罕见的遗传综合征。