The major goal of this research project is to identify and characterize genes involved in the pathogenesis of human kidney cancer. Our major accomplishments this year are: 1. We demonstrated that mutations in the MET proto- oncogene are responsible for a recently recognized inherited form of kidney cancer, hereditary papillary renal carcinoma (HPCR). In contrast to our previous studies with the von Hippel-Lindau disease gene, mutations in the MET proto-oncogene were all missense, and were located in the catalytic domain of the protein. Mutations in the MET proto-oncogene were detected in 6/7 HPRC families, and in a subset of sporadic papillary renal carcinomas. 2. We demonstrated that the mutations in MET produced a gain-of- function. The mutations in MET detected in patients with HPRC and sporadic tumors produced malignant transformation of NIH 3T3 cells. Constitutive phosphorylation of the MET protein was demonstrated in mouse cells transfected with mutant MET genes. 3. Some of the mutations detected in MET were located in residues homologous to those mutated in other receptor tyrosine kinases, RET and KIT. These results suggest that we have identified residues of the catalytic domain common to several receptor tyrosine kinases that in mutant form produce disease. 4. We have identified another distinct inherited form of renal neoplasia. So far, we have identified 5 families with multiple members affected with renal oncocytoma. Affected individuals have multiple, bilateral renal oncocytomas.
| Okimoto, Kazuo; Sakurai, Junko; Kobayashi, Toshiyuki et al. (2004) A germ-line insertion in the Birt-Hogg-Dube (BHD) gene gives rise to the Nihon rat model of inherited renal cancer. Proc Natl Acad Sci U S A 101:2023-7 |
| Schmidt, Laura S; Nickerson, Michael L; Angeloni, Debora et al. (2004) Early onset hereditary papillary renal carcinoma: germline missense mutations in the tyrosine kinase domain of the met proto-oncogene. J Urol 172:1256-61 |
| Linehan, W Marston; Vasselli, James; Srinivasan, Ramaprasad et al. (2004) Genetic basis of cancer of the kidney: disease-specific approaches to therapy. Clin Cancer Res 10:6282S-9S |
| Linehan, W Marston; Zbar, Berton (2004) Focus on kidney cancer. Cancer Cell 6:223-8 |
| Maranchie, Jodi K; Afonso, Anoushka; Albert, Paul S et al. (2004) Solid renal tumor severity in von Hippel Lindau disease is related to germline deletion length and location. Hum Mutat 23:40-6 |
| Lingaas, Frode; Comstock, Kenine E; Kirkness, Ewen F et al. (2003) A mutation in the canine BHD gene is associated with hereditary multifocal renal cystadenocarcinoma and nodular dermatofibrosis in the German Shepherd dog. Hum Mol Genet 12:3043-53 |
| Linehan, W Marston; Walther, McClellan M; Zbar, Berton (2003) The genetic basis of cancer of the kidney. J Urol 170:2163-72 |
| Zbar, Berton; Klausner, Richard; Linehan, W Marston (2003) Studying cancer families to identify kidney cancer genes. Annu Rev Med 54:217-33 |
| Toro, Jorge R; Glenn, Gladys; Hou, Lifang et al. (2003) Facial papules, spontaneous pneumothorax, and renal tumors. J Am Acad Dermatol 48:111-4 |
| Choyke, Peter L; Glenn, Gladys M; Walther, McClellan M et al. (2003) Hereditary renal cancers. Radiology 226:33-46 |
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