This proposal is approached from the perspective that cancer is a dynamic process which occurs as a result of an accumulation of dominant (activating) and recessive (loss of suppression) genetic alterations. We have applied this perspective to the investigation of the development of central nervous system (CNS) cancer in attempt to define those genes whose alteration are causally involved in the development of this type of neoplasia. The long-term objective of this investigation is to provide genetic compensation for such alterations to determine whether compensation results in suppression of cancer cell phenotypes in in vitro and in vivo model systems. To establish a basis for such experimentation, we are currently involved In the CNS tumor characterization of alterations to three genes. Specifically, these characterizations involve intragenic deletions of amplified epidermal growth factor receptor gene, base substitution (point mutation) of the p53 gene, and deletion of the interferon alpha and beta genes. In addition to these genes, our preliminary data suggest the existence of a novel tumor suppressor gene on chromosome l0 whose loss is essential to the attainment of high-grade CNS tumor malignancy. We are currently working and propose investigations directed towards the identification and isolation of this gene. Execution of the program of research proposed herein will result in significant basic and clinical science contributions as a consequence of information obtained concerning the functional and biological effects of specific gene mutations in CNS tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA055728-01
Application #
3200247
Study Section
Pathology A Study Section (PTHA)
Project Start
1991-05-01
Project End
1995-02-28
Budget Start
1991-05-01
Budget End
1992-02-29
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Smith, J S; Wang, X Y; Qian, J et al. (2000) Amplification of the platelet-derived growth factor receptor-A (PDGFRA) gene occurs in oligodendrogliomas with grade IV anaplastic features. J Neuropathol Exp Neurol 59:495-503
Frederick, L; Eley, G; Wang, X Y et al. (2000) Analysis of genomic rearrangements associated with EGRFvIII expression suggests involvement of Alu repeat elements. Neuro Oncol 2:159-63
Frederick, L; Wang, X Y; Eley, G et al. (2000) Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas. Cancer Res 60:1383-7
Raffel, C; Frederick, L; O'Fallon, J R et al. (1999) Analysis of oncogene and tumor suppressor gene alterations in pediatric malignant astrocytomas reveals reduced survival for patients with PTEN mutations. Clin Cancer Res 5:4085-90
Bredel, M; Pollack, I F; Hamilton, R L et al. (1999) Epidermal growth factor receptor expression and gene amplification in high-grade non-brainstem gliomas of childhood. Clin Cancer Res 5:1786-92
James, C D; Galanis, E; Frederick, L et al. (1999) Tumor suppressor gene alterations in malignant gliomas: histopathological associations and prognostic evaluation. Int J Oncol 15:547-53
Wang, X Y; Smith, D I; Frederick, L et al. (1998) Analysis of EGF receptor amplicons reveals amplification of multiple expressed sequences. Oncogene 16:191-5
Eley, G; Frederick, L; Wang, X Y et al. (1998) 3' end structure and rearrangements of EGFR in glioblastomas. Genes Chromosomes Cancer 23:248-54
Liu, W; Smith, D I; Rechtzigel, K J et al. (1998) Denaturing high performance liquid chromatography (DHPLC) used in the detection of germline and somatic mutations. Nucleic Acids Res 26:1396-400
Olson, J J; Barnett, D; Yang, J et al. (1998) Gene amplification as a prognostic factor in primary brain tumors. Clin Cancer Res 4:215-22

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