Molecular genetic analysis of von Hippel-Lindau disease

Abstract

Von Hippel-Lindau (VHL) disease is a dominantly inherited multisystem family cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal carcinoma, phaeochromocytoma, pancreatic islet cell tumours and endolymphatic sac tumours. In addition, renal, pancreatic and epididymal cysts occur. Morbidity and mortality from VHL disease can be reduced by the identification and surveillance of affected individuals and at-risk relatives so that complications are diagnosed at an early presymptomatic stage. The detailed mapping and subsequent isolation of the VHL tumour suppressor gene has enabled molecular genetic analysis in families and patients with definite or possible VHL disease. Initially, linked DNA markers were used in informative families to modify individual risks and then to make appropriate alterations in surveillance programs. However, currently most DNA analysis involves the characterisation of germline mutations. World-wide, mutations have been identified in almost 500 families (including 132 in our laboratory). These studies have revealed considerable heterogeneity both in the type and in the location of mutations within the VHL gene. In our experience, most recurrent mutations result from de novo mutations at hypermutable sequences, although a founder effect for the Tyr98His ('Black Forest') mutation has been reported in German and American families. Although many mutations are predicted to impair the ability of pVHL to combine with the elongin regulatory subunits, analysis of genotype-phenotype relationships suggests that the VHL protein has multiple and tissue specific functions. Calculation of tumour risks for different classes of VHL mutations has provided important prognostic information especially with respect to the likelihood of phaeochromocytoma. However, there is evidence that retinal involvement does not correlate with allelic heterogeneity, but that the variability in retinal angiomatosis is influenced by modifier gene effects. VHL gene mutation analysis also provides a basis for investigating the genetic basis of familial phaeochromocytoma and renal cell carcinoma, and apparently isolated retinal angiomas. Results to date suggest that a substantial proportion of patients with familial pheochromocytoma have VHL gene mutations but in contrast, most familial clusters of clear cell renal cell carcinoma (RCC) without evidence of VHL do not have germline VHL mutations.