SILENCING OF THE VHL TUMOR-SUPPRESSOR GENE BY DNA METHYLATION IN RENAL-CARCINOMA

Mutational inactivation and allelic loss of the von Hippel-Lindan (VHL ) gene appear to be causal events for the majority of spontaneous clea r-cell renal carcinomas. We now show that hypermethylation of a normal ly unmethylated CPG island in the 5' region provides another potential ly important mechanism for inactivation of the VHL gene in a significa nt portion of these cancers. This hypermethylation was found in 5 of 2 6 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with V HL hypermethylation had no detectable mutations, whereas one had a mis sense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in th is 5' CpG island, none of the 5 tumors expressed the VHL gene. In cont rast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal ce ll culture line, treatment with 5-aza-2'-deoxycytidine resulted in ree xpression of the VHL gene. These findings suggest that aberrant methyl ation of CpG islands may participate in the tumor-suppressor gene inac tivations which initiate or cause progression of common human cancers.