Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma.

TLDR

Mutational inactivation and allelic loss of the VHL gene are causal events in most spontaneous clear‑cell renal carcinomas. The study demonstrates that hypermethylation of a normally unmethylated CpG island in the 5′ region can inactivate the VHL gene in a significant portion of clear‑cell renal carcinomas. Hypermethylation of the VHL 5′ CpG island was found in 19% of tumors, correlated with loss of VHL expression, occurred independently of mutations, and could be reversed by demethylation, indicating methylation as an inactivation mechanism.

Abstract

Mutational inactivation and allelic loss of the von Hippel-Lindau (VHL) gene appear to be causal events for the majority of spontaneous clear-cell renal carcinomas. We now show that hypermethylation of a normally unmethylated CpG island in the 5' region provides another potentially important mechanism for inactivation of the VHL gene in a significant portion of these cancers. This hypermethylation was found in 5 of 26 (19%) tumors examined. Four of these had lost one copy of VHL while one retained two heavily methylated alleles. Four of the tumors with VHL hypermethylation had no detectable mutations, whereas one had a missense mutation in addition to hypermethylation of the single retained allele. As would be predicted for the consequence of methylation in this 5' CpG island, none of the 5 tumors expressed the VHL gene. In contrast, normal kidney and all tumors examined with inactivating VHL gene mutations but no CpG island methylation had expression. In a renal cell culture line, treatment with 5-aza-2'-deoxycytidine resulted in reexpression of the VHL gene. These findings suggest that aberrant methylation of CpG islands may participate in the tumor-suppressor gene inactivations which initiate or cause progression of common human cancers.