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Novel mutations of the MET proto-oncogene in papillary renal carcinomas
L Schmidt1, K Junker, N Nakaigawa
1Intramural Research Support Program, SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
Abstract:
Hereditary papillary renal carcinoma (HPRC) is characterized by multiple, bilateral papillary renal carcinomas. Previously, we demonstrated missense mutations in the tyrosine kinase domain of the MET proto-oncogene in HPRC and a subset of sporadic papillary renal carcinomas. In this study, we screened a large panel of sporadic papillary renal carcinomas and various solid tumors for mutations in the MET proto-oncogene. Summarizing these and previous results, mutations of the MET proto-oncogene were detected in 17/129 sporadic papillary renal carcinomas but not in other solid tumors. We detected five novel missense mutations; three of five mutations were located in the ATP-binding region of the tyrosine kinase domain of MET. One novel mutation in MET, V1110I, was located at a codon homologous to an activating mutation in the c-erbB proto-oncogene. These mutations caused constitutive phosphorylation of MET when transfected into NIH3T3 cells. Molecular modeling studies suggest that these activating mutations interfere with the intrasteric mechanism of tyrosine kinase autoinhibition and facilitate transition to the active form of the MET kinase. The low frequency of MET mutations in noninherited papillary renal carcinomas (PRC) suggests that noninherited PRC may develop by a different mechanism than hereditary papillary renal carcinoma.
Insights
Mutations in the MET proto-oncogene were found in sporadic papillary renal carcinomas, suggesting a distinct development pathway compared to hereditary forms. These MET mutations activate the kinase, potentially driving tumor growth.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Hereditary papillary renal carcinoma (HPRC) involves multiple, bilateral tumors.
- Previous research identified MET proto-oncogene mutations in HPRC and some sporadic cases.
Purpose of the Study:
- To screen sporadic papillary renal carcinomas and other solid tumors for MET proto-oncogene mutations.
- To investigate the functional impact of identified MET mutations.
Main Methods:
- Screening of sporadic papillary renal carcinomas and various solid tumors for MET mutations.
- Transfection of mutated MET into NIH3T3 cells to assess phosphorylation.
- Molecular modeling to understand the structural effects of mutations.
Main Results:
- MET proto-oncogene mutations were found in 17 out of 129 sporadic papillary renal carcinomas.
- No MET mutations were detected in other solid tumors analyzed.
- Five novel missense mutations were identified, with three in the ATP-binding region.
- A specific mutation, V1110I, homologous to an activating mutation in c-erbB, caused constitutive MET phosphorylation.
- Molecular modeling indicated these mutations disrupt kinase autoinhibition, promoting an active state.
Conclusions:
- The MET proto-oncogene is somatically mutated in a subset of sporadic papillary renal carcinomas.
- These mutations lead to constitutive activation of the MET kinase.
- The low frequency of MET mutations in non-hereditary PRC suggests alternative oncogenic mechanisms may be involved in their development.