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Promoter Methylation Status of Multiple Genes in Uveal Melanoma

From ¹The Krieger Eye Research Laboratory, Felsenstein Medical Research Center, Tel Aviv University, Petach Tikva, Israel; ²The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel; the ⁴Department of Gynecology, Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel; the ⁵Department of Ophthalmology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel; the ⁶Department of Ophthalmology, Pediatric Unit, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel; and ⁷Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

PURPOSE. Aberrant promoter hypermethylation of CpG islands is thought to play an important role in the inactivation of tumor-suppressor genes (TSGs) in cancer. Studies of cutaneous melanoma have reported a high methylation rate for MGMT, DAPK, RAR-b2, and RASSF1A. In colon cancer, SOCS-1, IGF-2, RUNX3, NEUROG1, and CACNA1G are commonly inactivated. The concomitant methylation of at least three of these genes may represent a distinct trait, the CpG island methylator phenotype (CIMP). The purpose of the present study was to investigate the role of epigenetic inactivation of multiple genes in uveal melanoma.

METHODS. Twenty samples of uveal melanoma were analyzed for the methylation status of nine candidate cancer-related genes: MGMT, DAPK, RAR-b2, RASSF1A, SOCS-1, IGF-2, RUNX3, NEUROG1, and CACNA1G, using real-time quantitative methylation-specific polymerase chain reaction after sodium bisulfite modification.

RESULTS. Methylation rates of the genes commonly inactivated in cutaneous melanoma were 70% for RASSFIA, 5% for MGMT and DAPK, and 0 for RAR-b2. The rates for the CIMP-related genes were 25% for RUNX3, 5% for NEUROG1 and CACNA1G, and 0 for SOCS-1 and IGF-2. None of the samples was CIMP-positive.

CONCLUSIONS. In this study uveal melanoma was negative for CIMP, with hypermethylation of RASSF1A. The negative CIMP phenotype and frequent RASSF1A methylation in uveal melanoma is in accord with its known lack of BRAF mutations. Given that mutations in genes of the RAS pathway are rarely observed in uveal melanoma, epigenetic inactivation of RASSF1A may be an alternative mechanism of tumorigenesis. The low frequency of promoter methylation of TSGs commonly inactivated in cutaneous melanoma further stratifies the different tumorigenesis pathway in cutaneous and uveal melanoma.

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				P A van der Velden and W Maat Methylation in uveal melanoma Br. J. Ophthalmol., January 1, 2009; 93(1): 132 - 132. [Full Text] [PDF]