Genetic Epidemiology of Familial Childhood Cancer

这个正在进行的项目的目标是识别和表征与癌症风险有关的基因。 家族性儿童肉瘤癌症综合征(Li Fraumeni综合征，LFS)和(新增 项目)肾母细胞瘤(WT)。对于每个综合征，我们都展示了与之相关的已知基因(P53 和WT1)，额外遗传贡献的证据，以及遗传异质性的证据。在家庭中 对于胚系p53突变，我们发现了性别和代际风险显著异质性的证据， 后代人发病年龄较小。我们有两种综合症的例子，在这两种症状中，我们 已经排除了p53或WT1作为易感基因的可能性，并发现了基因组中新的 可能会有所贡献。为了确定其他癌症易感基因和风险修饰物，我们建议使用数据 由持续的纵向研究产生，并从其他项目和岩心中执行合并 家族性儿童癌症综合征的遗传连锁和分离分析。该提案包括 使用回归Logistic模型、蒙特卡罗马尔可夫链方法、Kaplan Meier和比例 危险生存分析。我们将纳入端粒功能的测量，因为它们与癌症风险或 一种特定的基因型别。具体目标是(1)使用连锁和分离分析来识别其他 P53突变LFS家族中的风险修饰物，包括解释观察到的 世代效应和与多原发瘤相关的因素，并表征表型和 非P53癌倾向(LFS)家系的基因分型，(2)确定遗传和治疗相关的作用 肉瘤队列中多个额外肿瘤预后的危险因素，以及(3)确定 家族性肾母细胞瘤的遗传模型(S) 肾母细胞瘤的相关遗传途径。这些分析为项目提供了关于 新发现的基因组区域或基因的贡献。 癌症遗传易感性和第二原发癌的重要性，以罕见证候为例 2004年，NCI就这一主题举行了一次生存会议，表彰了这一主题。这款P01具有独特的 结合人类和小鼠遗传学识别新的癌症基因和遗传机制 易感性对人群以及罕见的遗传综合征都将是重要的。

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.