Cytogenetic studies, genetic linkage studies of familial melanoma kindreds and allelotyping of sporadic and familial melanomas suggested that genetic changes on the short arm of chromosome 9 near the IFN loci were causally implicated in malignant melanomas. LOH studies with a high density of 9p markers on cell liens and uncultured tumors of various types have recently focused attention on the region of 9p21 between ifna AND d9s171 loci nd because of common homozygous losses centered on a 40kb region in numerous tumor cell lines, including melanomas, the p16 gene (locus name CDKN2, aka MTSI, CDK41) was proposed as a candidate multiple tumor suppressor gene and, more specifically, as the 9p-linked familial malignant melanoma predisposing gene (MLM). Since we do not find frequent CDKN2 mutations in uncultured melanomas and germline mutations have been identified in only a fraction of 9p-linked familial melanoma kindreds, its role as the multiple tumor suppressor gene and as the major 9p21-linked MLM gene is not fully established. Ongoing allelotyping of sporadic melanomas and other tumor types have demonstrated more than one common region of loss in 9p21, suggesting the presence of more than one suppressor gene in this chromosome region. To investigate this complex situation in sporadic and familial melanomas we will pursue two major goals; 1. To clarify the role of p16, we will complete our investigation of the p16 gene in germline transmitted melanomas by following transmission of the mutant germline p16 genes in at least three families and, with our intraprogram colleagues, correlating mutant gene function with penetrance and severity of disease. The natural history of occurrence of specific p16 mutations in sporadic and familial melanomas with serve as a basis for screening and, possible, therapeutic strategies. 2. To identify another 9p21-linked melanoma suppressor gene, we will refine our LOH map 9p21 using primary, uncultured melanoma samples, clone candidate genes from YAC and cosmid contigs, identify the second suppressor gene by analysis in melanoma kindreds and investigate its function, in collaboration with Project 1,2 and 4 investigators. The long range goal is to use our unique collection of malanoma families and cases, in combination with the defined MLM gene mutations, to devise therapeutic strategies, in collaboration with our program leaders and with the jefferson Cancer Center Melanoma Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA021124-18
Application #
6236420
Study Section
Project Start
1997-07-08
Project End
1998-05-31
Budget Start
1996-10-01
Budget End
1997-09-30
Support Year
18
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Thomas Jefferson University
Department
Type
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107
Russell, John P; Engiles, Julie B; Rothstein, Jay L (2004) Proinflammatory mediators and genetic background in oncogene mediated tumor progression. J Immunol 172:4059-67
Powell Jr, Daniel J; Eisenlohr, Laurence C; Rothstein, Jay L (2003) A thyroid tumor-specific antigen formed by the fusion of two self proteins. J Immunol 170:861-9
Cornetta, Anthony J; Russell, John P; Cunnane, Mary et al. (2002) Cyclooxygenase-2 expression in human thyroid carcinoma and Hashimoto's thyroiditis. Laryngoscope 112:238-42
Zanesi, N; Fidanza, V; Fong, L Y et al. (2001) The tumor spectrum in FHIT-deficient mice. Proc Natl Acad Sci U S A 98:10250-5
Podolski, J; Byrski, T; Zajaczek, S et al. (2001) Characterization of a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. J Hum Genet 46:685-93
Druck, T; Podolski, J; Byrski, T et al. (2001) The DIRC1 gene at chromosome 2q33 spans a familial RCC-associated t(2;3)(q33;q21) chromosome translocation. J Hum Genet 46:583-9
Powell Jr, D J; Russell, J P; Li, G et al. (2001) Altered gene expression in immunogenic poorly differentiated thyroid carcinomas from RET/PTC3p53-/- mice. Oncogene 20:3235-46
Daheron, L; Zenz, T; Siracusa, L D et al. (2001) Molecular cloning of Ian4: a BCR/ABL-induced gene that encodes an outer membrane mitochondrial protein with GTP-binding activity. Nucleic Acids Res 29:1308-16
Falvella, F S; Menegola, E; Giavini, E et al. (2000) Expression of Fhit protein during mouse development. Anat Rec 260:208-11
Russell, J P; Powell, D J; Cunnane, M et al. (2000) The TRK-T1 fusion protein induces neoplastic transformation of thyroid epithelium. Oncogene 19:5729-35

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