A Mutational Model for Childhood Cancer

描述（由申请人提供）：该计划的总体目标是确定易患儿童癌症的基因，肿瘤发展的分子途径和临床意义。我们已经集中在两个模型家族综合征的儿童和青少年癌症，肉瘤和李Fraumeni综合征（LFS）及其变种，肾母细胞瘤。我们开发了一个多学科计划，利用遗传流行病学、分子遗传学和基因组学的综合技术，应用于该计划中开发的癌症易感家族和小鼠模型的丰富资源，研究儿童和相关癌症的遗传易感性。这些假设是基于癌症的多阶段模型。对于每种肿瘤类型，已经鉴定出可以作为生殖系突变和肿瘤特异性突变两者改变的遗传基因座。还有其他癌症易感基因和风险修饰因子的重要证据，包括世代效应，至少对于LFS。该计划的基本主题包括识别潜在的癌症易感基因和风险修饰因子，通过类型和机制分析生殖细胞和体细胞突变，确定肿瘤的分子遗传解剖，开发人类癌症易感综合征的动物模型，确定端粒功能在LFS和小鼠模型中癌症风险中的作用，并确定生殖系突变对患者及其家属的影响。该项目的研究结果应该为癌症发生机制提供见解，并为癌症高危患者的临床项目提供指导。

DESCRIPTION (provided by applicant): The overall goal of the program is to identify genes that predispose to childhood cancer, the molecular pathways to tumor development, and the clinical implications. We have focused on two model familial syndromes of childhood and adolescent cancers, sarcomas and Li Fraumeni Syndrome (LFS) and its variants, and Wilms' tumor of the kidney. We have developed a multidisciplinary program to investigate genetic susceptibility to childhood and associated cancer using integrated technology of genetic epidemiology, molecular genetics and genomics applied to the rich resources of cancer prone families and mouse models developed in this program. The hypotheses are based on a multi-stage model for cancer. For each tumor type, genetic loci have been identified that may be altered both as germline mutations and as tumor-specific mutations. There is also significant evidence for additional cancer susceptibility genes and risk modifiers, including an effect of generation, at least for LFS. The underlying themes of the program include identification of the underlying cancer susceptibility genes and risk modifiers, analysis of germline and somatic mutations by type and mechanism, determination of the molecular genetic anatomy of the tumors, development of animal models for human cancer susceptibility syndromes, determination of the role of telomere function in cancer risk in LFS and mouse models, and determination of the implications of germline mutations for the patients and their families. The findings from this program should provide insights into the mechanisms of carcinogenesis as well as guidelines for clinical programs for patients at high risk of cancer.