MET – Papillary Renal Cell Carcinoma

Germline missense mutation c.3274G>A (p.Val1092Ile) in the ATP‐binding site of MET segregates with disease in a kindred with hereditary papillary RCC (PMID:10417759). No pathogenic germline MET mutations were identified in a clinic‐based cohort of 59 sporadic PRCC cases, indicating low prevalence outside familial settings (PMID:11551094). Somatic MET kinase domain mutations, including p.Val1092Ile, are observed in sporadic and familial PRCC, underscoring MET’s role in disease pathogenesis.

Functional studies reveal that MET mutants exhibit increased autophosphorylation, enhanced kinase activity, and transforming capacity in NIH-3T3 cells (PMID:9326629, PMID:9826715). In vivo mouse models with activating MET mutations develop carcinomas and metastases, paralleling human PRCC features (PMID:15557554). These data support a gain-of-function mechanism of MET in pRCC.

Key take-home: Activating MET kinase domain mutations confer hereditary and sporadic susceptibility to papillary RCC, guiding genetic testing and targeted therapeutic strategies.

References

• International journal of cancer • 1999 • Novel mutation in the ATP-binding site of the MET oncogene tyrosine kinase in a HPRCC family. PMID:10417759
• Genetic testing • 2001 • Papillary renal cell carcinoma: analysis of germline mutations in the MET proto-oncogene in a clinic-based population. PMID:11551094
• Proceedings of the National Academy of Sciences of the United States of America • 1997 • Activating mutations for the met tyrosine kinase receptor in human cancer. PMID:9326629
• Proceedings of the National Academy of Sciences of the United States of America • 1998 • The mutationally activated Met receptor mediates motility and metastasis. PMID:9826715
• Proceedings of the National Academy of Sciences of the United States of America • 2004 • Activating Met mutations produce unique tumor profiles in mice with selective duplication of the mutant allele. PMID:15557554

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