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的是识别和表征导致癌症风险的基因 肉瘤的家族性儿童癌症综合征（Li Fraumeni综合征，LFS）和（涉及的新添加 项目）威尔姆斯的肿瘤（WT）。对于每种综合征，我们都证明了已知的基因（p53） 和WT1），证据，证明了额外的遗传贡献，以及遗传异质性的证据。在家庭中 通过种系p53突变，我们发现证据表明性别和发电的风险存在显着异质性， 连续几代人的发病年龄较小。我们有两个综合症的例子 排除了p53或WT1为易感基因座，并确定了基因组的新区域 可能会做出贡献。为了识别其他癌症敏感性基因和风险修饰符，我们建议使用数据 由持续的纵向研究以及其他项目和核心产生 家族性儿童癌综合征中的遗传连锁和分离分析。该提案包括 使用回归逻辑模型，Monte Carlo Markov链方法，Kaplan Meier和比例 危害生存分析。我们将在与癌症风险相关或 给定的基因型。具体目的是（1）使用链接和隔离分析以确定其他 p53突变LFS中的风险修饰符，包括要考虑观察到的机制 与多个原发性肿瘤相关的产生效应和因素，并表征表型和 非p53癌症（LFS）的基因型，（2）确定遗传和治疗相关的作用 肉瘤队列中多个其他肿瘤结果的风险因素，（3）确定 最能表征家族性威尔姆斯肿瘤的遗传模型，并为鉴定 威尔姆斯肿瘤中的相关遗传途径。这些分析为项目提供了有关项目的反馈 新确定的基因组区域或基因的贡献。 使用稀有综合症作为癌症遗传易感性和第二​​次原发性癌症的重要性 模型，在2004年的NCI幸存会议上得到了认可。该P01具有独特的 人类和小鼠遗传学以鉴定癌症的新基因和遗传机制的结合 对种群以及罕见的遗传综合征的敏感性将很重要。