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 objectives of Core E are: (1) to genotype constitutive DNA samples for genome-wide? linkage and association studies, (2) to allelotype on a genome-wide or targeted basis matched? normal/tumor DNA sample pairs for tumor-specific loss of constitutive heterozygosity (LOH), (3) to? maintain a functioning genotype database, and (4) to conduct genetic analyses on the obtained? genotype data. To this end, human genomic DNA samples of individuals from cancer families ascertained? by Dr. Strong (Core B) segregating either soft tissue sarcomas (STS) or osteosarcomas (OST) and? classified as having Li-Fraumeni syndrome (LFS) or one of its variants (Dr. Strong/Project 1 and Dr.? Krahe/Project 2), or Wilms' tumor (Dr. Huff/Project 4) will be analyzed using various complementing high-throughput? technologies integrating microsatellite and single nucleotide polymorphism (SNP) markers to? identify genomic regions co-segregating with the disease (Projects 1 and 2) and to confirm regions of LOH? (Projects 2 and 4). Genotyping platforms include fluorescent technology with highly informative? microsatellite markers in optimized panels for genome-wide genotyping and custom markers using a? universal primer approach for regional fine mapping (Projects 1, 2, and 4). High-density SNP microarrays? (approximately 10,000 or about 100,000 SNPs) will be used to genotype individuals in both p53 and non-p53 families to identify modifier genes of tumor susceptibility (Projects 1 and 2) and to allelotype matched normal/tumor DNA? sample pairs to identify regions of tumor-specific loss of constitutive heterozygosity (Projects 1 and 2).? Pyrosequencing will be used to type additional SNP markers in targeted regions identified by the above? approaches for fine mapping (Projects 1, 2, and 4). The obtained human genotype data will be analyzed for? genetic linkage and association by complementing parametric and non-parametric analysis methods. For? these analyses, Core E will interact closely with the Statistical Genetics and Bioinformatics Core (Core C)? headed by Dr. Amos. The ultimate goals are to map major cancer susceptibility genes and modifier genes? that underlie the observed increased segregation of certain cancers in the families studied by Drs. Strong? (Projects 1, Core B), Krahe (Project 2), and Huff (Project 4), to map and identify modifiers of tumor? susceptibility (Projects 1 and 2), and to identify additional genomic regions that may be involved in tumor? development and/or progression by providing LOH information (Project 2).

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA034936-20
Application #
7418593
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
20
Fiscal Year
2007
Total Cost
$313,934
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Peng, Gang; Bojadzieva, Jasmina; Ballinger, Mandy L et al. (2017) Estimating TP53 Mutation Carrier Probability in Families with Li-Fraumeni Syndrome Using LFSPRO. Cancer Epidemiol Biomarkers Prev 26:837-844
Maturu, Paramahamsa; Jones, Devin; Ruteshouser, E Cristy et al. (2017) Role of Cyclooxygenase-2 Pathway in Creating an Immunosuppressive Microenvironment and in Initiation and Progression of Wilms' Tumor. Neoplasia 19:237-249
Huang, Le; Mokkapati, Sharada; Hu, Qianghua et al. (2016) Nephron Progenitor But Not Stromal Progenitor Cells Give Rise to Wilms Tumors in Mouse Models with ?-Catenin Activation or Wt1 Ablation and Igf2 Upregulation. Neoplasia 18:71-81
Palculict, Timothy Blake; Ruteshouser, E Cristy; Fan, Yu et al. (2016) Identification of germline DICER1 mutations and loss of heterozygosity in familial Wilms tumour. J Med Genet 53:385-8
Liu, Changlu; Ma, Jianzhong; Amos, Christopher I (2015) Bayesian variable selection for hierarchical gene-environment and gene-gene interactions. Hum Genet 134:23-36
Mokkapati, Sharada; Niopek, Katharina; Huang, Le et al. (2014) ?-catenin activation in a novel liver progenitor cell type is sufficient to cause hepatocellular carcinoma and hepatoblastoma. Cancer Res 74:4515-25
Quintás-Cardama, Alfonso; Post, Sean M; Solis, Luisa M et al. (2014) Loss of the novel tumour suppressor and polarity gene Trim62 (Dear1) synergizes with oncogenic Ras in invasive lung cancer. J Pathol 234:108-19
Maturu, Paramahamsa; Overwijk, Willem W; Hicks, John et al. (2014) Characterization of the inflammatory microenvironment and identification of potential therapeutic targets in wilms tumors. Transl Oncol 7:484-92
Shahidul Makki, Mohammad; Cristy Ruteshouser, E; Huff, Vicki (2013) Ubiquitin specific protease 18 (Usp18) is a WT1 transcriptional target. Exp Cell Res 319:612-22
Kaftanovskaya, Elena M; Neukirchner, Giselle; Huff, Vicki et al. (2013) Left-sided cryptorchidism in mice with Wilms' tumour 1 gene deletion in gubernaculum testis. J Pathol 230:39-47

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