Mutations of the VHL gene in sporadic renal cell carcinoma: Definition of a risk factor for VHL patients to develop an RCC

To investigate the nature of somatic von Hippel-Lindau (VHL) mutations, we analyzed 173 primary sporadic human renal cell carcinomas for mutations of the VHL tumor suppressor gene, using polymerase chain reaction (PCR) and si ngle-strand conformational polymorphism analysis (SSCP) of DNA, We detected abnormal SSCP pattern in 73 samples. After sequencing, we identified micro deletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8% , and missense mutations in 17%, Among these mutations, 50% correspond to n ew mutations. VHL mutations were found only in the nonpapillary renal cell carcinoma (RCC) subtype, as previously reported. To compare somatic and ger mline mutations, we used the VHL database, which in eludes 507 mutations. T he study of mutational events revealed a significant difference between som atic and germline mutations with mutations leading to truncated proteins ob served in 78% of somatic mutations vs only 37% in germline mutations (P < 0 .001). We postulated that a specific pattern of VHL mutations is associated with sporadic RCC, This pattern corresponds to mutations leading mainly to truncated proteins with few specific missense mutations. We then analyzed the occurrence of RCC in VHL families, based on the nature of mutations. We observed RCC in at least one member of the VHL families in 77% of cases wi th mutations leading to truncated proteins versus 55% in cases with missens e mutations (P < 0.05). Thus, mutations resulting in truncated proteins may lead to a higher risk of RCC in VHL patients. Hum Mutat 13:464-475, 1999, (C) 1999 Wiley-Liss, Inc.