A Mutational Model for Childhood Cancer

描述（由申请人提供）：该项目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及其临床意义。我们专注于儿童和青少年癌症的两种模式家族综合征，肉瘤和李氏综合征（LFS）及其变体，以及肾威尔姆斯肿瘤。我们开发了一个多学科项目，利用遗传流行病学、分子遗传学和基因组学的综合技术，研究儿童和相关癌症的遗传易感性，并将其应用于该项目开发的癌症易感家族和小鼠模型的丰富资源。这些假设是基于癌症的多阶段模型。对于每一种肿瘤类型，已经确定的基因位点可能被改变为种系突变和肿瘤特异性突变。还有重要的证据表明，至少对LFS来说，存在额外的癌症易感基因和风险调节剂，包括产生的影响。该项目的基本主题包括确定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种系和体细胞突变，确定肿瘤的分子遗传解剖结构，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。该项目的研究结果将为癌症发生的机制提供深入的见解，并为癌症高风险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.