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

James G. Herman, Farida Latif, Yongkai Weng, Michael I. Lerman, Berton Zbar, Sue Liu, Dvorit Samid, Dah Shuhn R Duan, James R. Gnarra, W. Marston Linehan, Stephen B Baylin

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)9700-9704
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume91
Issue number21
DOIs
StatePublished - Oct 11 1994

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DNA Methylation
Tumor Suppressor Genes
CpG Islands
Carcinoma
Kidney
Methylation
Neoplasms
Genes
decitabine
Alleles
Mutation
Loss of Heterozygosity
Gene Silencing
Missense Mutation
Renal Cell Carcinoma
Cell Culture Techniques
Cell Line

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. / Herman, James G.; Latif, Farida; Weng, Yongkai; Lerman, Michael I.; Zbar, Berton; Liu, Sue; Samid, Dvorit; Duan, Dah Shuhn R; Gnarra, James R.; Linehan, W. Marston; Baylin, Stephen B.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 91, No. 21, 11.10.1994, p. 9700-9704.

Research output: Contribution to journalArticle

Herman, JG, Latif, F, Weng, Y, Lerman, MI, Zbar, B, Liu, S, Samid, D, Duan, DSR, Gnarra, JR, Linehan, WM & Baylin, SB 1994, 'Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma', Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 21, pp. 9700-9704. https://doi.org/10.1073/pnas.91.21.9700
Herman, James G. ; Latif, Farida ; Weng, Yongkai ; Lerman, Michael I. ; Zbar, Berton ; Liu, Sue ; Samid, Dvorit ; Duan, Dah Shuhn R ; Gnarra, James R. ; Linehan, W. Marston ; Baylin, Stephen B. / Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. In: Proceedings of the National Academy of Sciences of the United States of America. 1994 ; Vol. 91, No. 21. pp. 9700-9704.
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