Abstract

The objective of this research is to elucidate genetic mechanisms underlying carcinogenesis in an animal model. The model is hereditary renal carcinoma in the rat. This dominantly inherited predisposition to cancer closely resembles the many such predispositions known in man, but seems to be the only such in an experimental animal. Furthermore, an acquired form of the disease occurs spontaneously or following irradiation or exposure to chemicals, and is pathologically identical to the hereditary form. This model may therefore be relevant for understanding the mechanism of induction of both hereditary and acquired cancers in man.
The specific aims are to (1) Determine the nature of the acquired mutation(s) responsible for the occurrence of renal carcinoma in the genetically predisposed rat, (2) Examine the role of the renal carcinoma locus in embryonic development and in radiation carcinogenesis, and (3) Identify and clone the renal carcinoma locus. The procedures to be used will include matings with an unrelated inbred strain, irradiation, surgery, pathologic examination, cytogenetic analysis, and molecular genetic techniques. Southern blotting, polymorphic DNA restriction fragments, molecular cloning, and insertional mutagenesis will be utilized in an attempt to understand the molecular mechanism of carcinogenesis in this model and to clone the renal carcinoma gene.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA043211-03
Application #
3185268
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1986-08-01
Project End
1989-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost

  Institution

Name
Institute for Cancer Research
Department
Type
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19111

  Publications

Yeung, R S; Xiao, G H; Jin, F et al. (1994) Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene. Proc Natl Acad Sci U S A 91:11413-6
Witzgall, R; Volk, R; Yeung, R S et al. (1994) Genomic structure and chromosomal location of the rat gene encoding the zinc finger transcription factor Kid-1. Genomics 20:203-9
Hino, O; Klein-Szanto, A J; Freed, J J et al. (1993) Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci U S A 90:327-31
Hino, O; Testa, J R; Buetow, K H et al. (1993) Universal mapping probes and the origin of human chromosome 3. Proc Natl Acad Sci U S A 90:730-4
Yeung, R S; Taguchi, T; Patriotis, C et al. (1993) New markers, D16FC1 and Tp12, differentiate between rat chromosomes 16 and 17. Cytogenet Cell Genet 62:149-52
Yeung, R S; Buetow, K H; Testa, J R et al. (1993) Susceptibility to renal carcinoma in the Eker rat involves a tumor suppressor gene on chromosome 10. Proc Natl Acad Sci U S A 90:8038-42
Yeung, R S; Hino, O; Vilensky, M et al. (1993) Assignment of 22 loci in the rat by somatic hybrid and linkage analysis. Mamm Genome 4:585-8
Knudson Jr, A G (1993) Introduction to the genetics of primary renal tumors in children. Med Pediatr Oncol 21:193-8
Knudson, A G (1992) Heredity and environment in the origin of cancer. Prog Clin Biol Res 376:31-40
Testa, J R; Taguchi, T; Knudson, A G et al. (1992) Localization of the interferon-alpha gene cluster to rat chromosome bands 5q31----q33 by fluorescence in situ hybridization. Cytogenet Cell Genet 60:247-9

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