A Mutational Model for Childhood Cancer

一个儿童癌症的突变模型 路易斯·C坚强，医学博士。 该项目的总体目标是确定易患儿童癌症的基因， 肿瘤发展的途径和临床意义。我们关注了两个典型的家庭 儿童和青少年癌症、肉瘤和Li Fraumeni综合征（LFS）及其变体的综合征， 和肾母细胞瘤我们已经开发了一个多学科的项目来研究遗传 利用遗传流行病学综合技术， 分子遗传学和基因组学应用于癌症易感家族和小鼠模型的丰富资源 在这个项目中开发的。这些假设是基于癌症的多阶段模型。对于每个肿瘤 类型，遗传基因座已被确定，可以改变作为生殖系突变和肿瘤特异性 突变。还有重要的证据表明，还有其他癌症易感基因和风险修饰因子， 包括产生的影响，至少对于LFS是这样。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，生殖细胞和体细胞突变的分析 类型和机制，确定肿瘤的分子遗传解剖， 人类癌症易感性综合征的动物模型，端粒功能在 LFS和小鼠模型中的癌症风险，以及确定生殖系突变对 患者及其家属。 该项目的研究结果应能提供对致癌机制的深入了解， 癌症高危患者的临床计划指南。

A MUTATIONAL MODEL FOR CHILDHOOD CANCER Louise C. Strong, M.D. 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.