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E. Merhavi, B. R. Avraham, Y. Cohen, S. Frenkel, I. Chowers, J. Pe’er, N. Goldenberg-Cohen; Promoter Methylation Status of Multiple Genes in Uveal Melanoma. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4771.
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© ARVO (1962-2015); The Authors (2016-present)
Aberrant promoter hypermethylation of CpG islands is thought to play an important role in the inactivation of tumor supressor genes (TSG) in cancer. In cutaneous melanoma, high methylation rate for O6-methylguanine DNA methyltransferase (MGMT), death-associated protein-kinase gene (DAP-kinase) and RARB2, and RASSF1A was previously reported. As uveal melanoma (UM) may resemble cutaneous melanoma and share the same origin from the neural crest, we suggest determining the role of epigenetic silencing of these genes in UM. To further explore the role of epigenetic genes inactivation in UM, we investigated the methylation status of SOCS-1, IGF-2, RUNX3, NEUROG1 and CACNA1G commonly inactivated in other human tumors. Methylation of at least 3 of these genes may represent a distinct trait referred to as CpG island methylator phenotype (CIMP). CIMP is considered to be a charaterstic feature for the serrated pathway of human tumorigenesis. In this study, we sought to investigate the role of epigenetic inactivation of multiple genes in UM.
We investigated the methylation status of 9 candidate cancer-related genes that are frequently epigenetically inactivated in melanoma: MGMT, DAP-K, RARB2, RASSF1A and CIMP related genes: SOCS-1, IGF-2, RUNX3, NEUROG1 and CACNA1G by real time Quantitative Mehylation Specific PCR (QMSP) analysis, after sodium bisulfite modification in 20 UM samples.
The methylation status of genes commonly inactivatd in cutaneous melanoma was 5% in MGMT, 5% in DAP-kinase, none in RARB2, and 71% in RASSF1A. None of our samples presented CIMP positive phenotype. We observed methylation in RUNX3 (25%), NEUROG1 (5%), and CACNA1G (5%). No methylation in SOCS-1 and IGF-2.
High frequency of promotor hypermethylation was detected only for RASSF1A. Given the fact that mutations in genes of the RAS pathway are rarely observed in UM, epigenetic inactivation of RASSF1A may be an alternative mechanism for formation of UM. The low frequency of promotor methylation of TSG commonly inactivated in cutaneous melanoma further stratified the different tumorigenesis pathway between these tumors. The negative CIMP in UM is in accord with the lack of BRAF mutations previously described, which is correlated to positive CIMP tumors.
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