Papillary renal cell carcinoma: Analysis of germline mutations in the MET proto-oncogene in a clinic-based population

Approximately 10% of all renal cell carcinomas (RCCs) present a distinctive papillary histology. Familial papillary RCC (PRCC) has been described, but the majority of cases appear to be sporadic. Recently, germline mutations in the MET proto-oncogene on chromosome 7 have been identified in families with hereditary PRCC. We evaluated 59 patients with PRCC for the frequency of MET germline mutations to determine the value of genetic screening of th is patient population. Between 1976 and 1997, 165 patients were identified with PRCC by retrospective chart review. Fifty-nine of 133 surviving patien ts agreed to provide a family history, a blood specimen, and informed conse nt for genetic research. DNA was isolated from peripheral blood leukocytes. Denaturing high-performance liquid chromatography (DHPLC) followed by geno mic sequencing was performed on eight exons of the MET proto-oncogene, incl uding exons 5-7 of the extracellular domain, exon 14, and exons 16-19 of th e tyrosine kinase domain. The 59 patients in this study included 49 men and 10 women with a mean age at diagnosis of 61 years. Bilateral and/or multif ocal disease was present in 13 cases (22%). No germline mutations were dete cted in the studied exons of the MET proto-oncogene (exons previously repor ted to contain deleterious mutations in familial PRCC). No pathological MET proto-oncogene germline mutations were identified in 59 patients with PRCC . The germline mutation rate in this clinic-based population of individuals with PRCC approaches 0% (CI = 0-6.18). MET proto-oncogene germline mutatio n screening does not appear to be clinically indicated in patients with PRC C without additional evidence for a genetic predisposition (positive family history, unusual age at onset, bilateral disease).