The broad, long-term objectives of the High Throughput Genotyping and Genetic Linkage Analysis Facility (Core E) are to provide the members of the program and their projects with a state-of-the-art facility for high throughput, automated genotyping and genetic linkage analysis for the mutation epidemiology of childhood tumors.
The specific aims of Core E are: (1) to genotype constitutive DNA samples for genome wide linkage analyses, (2) to allelotype on a targeted, genome-wide basis matched normal and tumor DNA samples for possible microsatellite instability (MSI), (4) to provide sequence analysis for TP53 mutations on DNA samples from paraffin embedded fixed tumor tissues, using the p53 GeneChip, (5) to maintain a functioning genotype database, and (6) to conduct genetic linkage analysis on the obtained genotype data. To this end, human genomic DNA samples of individuals from cancer families ascertained by Dr. Strong (Projects 1 and B) segregating either soft tissue sarcomas (STS) or osteosarcomas (OST) that have been shown to be negative for mutations in the TP53 tumor suppressor gene (Project 4), or Wilms tumor (WT, Project 2), will be analyzed using fluorescent technology and optimized panels of highly informative microsatellite markers. In addition, we will identify samples exhibiting MSI for Dr. Siciliano's (Project 5) study on genome instability and pass on him possible MSI information for quantitative analysis of this phenomenon. Similarly, mouse genomic DNA samples from inbred transgenic mice, which have been generated by Dr. Lozano (Project 4) and serve as a suitable murine model for human cancers, will be systematically genotyped. The obtained human genotype data will be analyzed for genetic linkage by complementing parametric and non- parametric linkage analysis. For the linkage analyses, Core E will interact closely with the main Linkage Analysis Facility in the Informatics and Analysis Core (Core C),, which is headed by Dr. Amos. The ultimate goals are to map the cancer susceptibility/tumor suppressor gene(s) underlying the observed increased segregation of certain cancers in the families studied by Drs. Strong (Projects 1, Core B), Huff (Project 2), and Lozano (Project 4), and to identify in the transgenic inbred mice a modifier gene for cancer susceptibility, which has been uncovered by Dr. Lozano (Project 4) and termed modifier of p53 (mop1). In addition, Core E will assist Dr. Huff (Project 2) in the identification of additional WT susceptibility gene region(s) by providing L0H information.
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