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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
3P01CA034936-23S1
Application #
8054035
Study Section
Subcommittee G - Education (NCI)
Program Officer
Ogunbiyi, Peter
Project Start
1997-08-01
Project End
2012-09-30
Budget Start
2010-05-01
Budget End
2012-09-30
Support Year
23
Fiscal Year
2010
Total Cost
$60,169
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pediatrics
Type
Other Domestic Higher Education
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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