Hereditary Papillary Renal Cell Carcinoma via the MET Gene

Renal cell carcinoma (RCC) is the most common kidney cancer representing approximately 95% of all renal tumors. RCC includes three different subtypes: clear cell (ccRCC, 75% of RCC), papillary (pRCC, 10%), and chromophobe (chRCC, 5%) (Hagenkord et al. Cancer Genetics 204:285-297, 2011). Most kidney cancers occur sporadically, but approximately 2-4% of renal tumors show familial inheritance (Axwijk et al. Eur J Clin Invest 40:433-439, 2010). Hereditary Papillary Renal Cell Carcinoma (HPRCC) is the familial inheritance of papillary renal tumors, which are often multifocal and bilateral, and have a typical age of onset of 50 to 70 years (Zbar et al. J Urol 151:561– 6, 1994). Papillary renal carcinomas have been morphologically divided into small (type 1) and large (type 2) cell tumors. HPRCC leads to type 1 renal cell carcinomas. Individuals with type 1 pRCC have been shown to have significantly better survival than individuals with type 2 pRCCs. The kidney is the only organ affected in HPRCC, and although the tumors are usually well differentiated, they are malignant and can metastasize with poor prognosis. HPRCC is caused by mutations in the proto-oncogene MET, and targeting the oncogenic form with administration of tyrosine kinase inhibitors combined with conventional chemo- and radio-therapies is currently being investigated (Salvi et al. International Journal of Oncology 33: 271-276, 2008).

HPRCC shows an autosomal dominant pattern of inheritance and is highly penetrant. Mutations in the MET oncogene lead to ligand-independent activation of the tyrosine kinase domain of the protein, which leads to constitutive activation of the hepatocyte growth factor (HGF)/c- Met pathway (Coleman and Russo. Current Opinion in Urology 19:478–485, 2009). Gain of function mutations lead to increases in cellular proliferation, neovascularization, and cell motility. Mutations in MET are also observed in sporadic papillary renal carcinomas (Hagenkord et al. Cancer Genetics 204:285-297, 2011). Reported germline MET mutations that correlate to HPRCC are missense, and are mostly located within the tyrosine kinase domain (Salvi et al. International Journal of Oncology 33: 271-276, 2008).

Analytical sensitivity should be high because the mutations reported are readily detectable by gene sequencing. Clinical sensitivity of MET mutations in HPRCC is unknown at this time.

This test provides full coverage of all coding exons of the MET gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.