We have developed a multidisciplinary program to investigate genetic events leading to childhood cancer using molecular, cytogenetic, and genetic epidemiologic techniques. The hypotheses are based on a multistage model for cancer. The overall goal is to investigate the role of each of 3 classes of genes in childhood cancer, including a) those genes which are inherited in an autosomal dominant manner and predispose to tumor, but permit tumor development at the cellular level in a recessive manner, after loss of the wild type allele; b) those genes which affect the mutation rate, affecting the frequency of initiated mutations as in class 1 or 3 genes, or of subsequent events such as recombination, deletion, insertion, amplification, etc; c) those genes (oncogenes) associated with tumor-specific activation and cell transformation, exerting an active or dominant effect at the cell level. To date we have defined a familial cancer syndrome attributable to a rare autosomal dominant gene which may account for 6 to 7% of childhood soft tissue sarcoma, and may account for most second malignant neoplasms. We are now trying to map the gene by genetic linkage in families, and to determine whether the genetic abnormality is associated with differential transforming activity. We will determine whether the same or other genetic factors are involved in adolescent soft tissue sarcoma, and in osteosarcoma, by survey and segregation analysis of the family history of cancer of those patients. Studies of a presumed class 1 gene for Wilms' tumor on 11p have revealed that most typical Wilms' tumors show loss of heterozygosity specific for chromosome 11p. This loss occurs by various mechanisms, including chromosome loss, chromosome 11p deletion, and most often somatic recombination. Further studies will define the frequency of each mechanism and the critical DNA sequences involved. To study class 2 genes, 6 different human DNA repair genes which complement CHO DNA repair mutants have been identified and localized to specific chromosomes. We will further characterize and map these genes regionally, determine the frequency of polymorphism for these genes and examine their role in genetic predisposition to childhood cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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University of Texas MD Anderson Cancer Center
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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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