A MUTATIONAL MODEL FOR CHILDHOOD CANCER

总体描述（申请人的描述）我们已经开发了一个多学科的项目，使用遗传流行病学、细胞和分子技术来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，并在儿童和青少年癌症的两个模型家族综合征，肉瘤和Li Fraumeni综合征及其变体和肾母细胞瘤中进行了测试。或每种肿瘤类型，已经鉴定了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。也有重要的证据表明遗传异质性，或涉及其他癌症易感性基因座。该计划的基本主题包括表征潜在癌症易感性的基本特征，确定对每种肿瘤的遗传贡献，确定基因组不稳定性的作用和性质以及赋予家族性癌症综合征基因组不稳定性的基因，按类型和机制分析种系和体细胞突变，开发人类癌症易感综合征的动物模型，以探索修饰基因和发育效应的证据，并确定生殖系突变对患者及其家庭的影响。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。

Overall Description (Applicant's Description) We have developed a multi- disciplinary program to investigate genetic susceptibility to childhood and associated cancer using genetic epidemiologic, cellular, and molecular techniques. The hypotheses are based on a multi-stage model for cancer, and are tested in two model familial syndromes of childhood and adolescent cancers, sarcomas and Li Fraumeni syndrome and its variants and Wilms' tumor of the kidney. or 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 genetic heterogeneity, or involvement of additional cancer susceptibility loci. The underlying themes of the program include characterization of the underlying characterization of the underling cancer susceptibility, determination of the heritable contribution to each tumor, determination of the role and nature of genomic instability and genes that confer genomic instability in familial cancer syndromes, analysis of germline and somatic mutations by type and mechanism, development of animal models for human cancer susceptibility syndromes to explore evidence for modifier genes and developmental effects, 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.