Genetic Epidemiology of Familial Childhood Cancer

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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.