1. Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma
- Author
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Pa, Velden, Ja, Metzelaar-Blok, Bergman W, Monique H, Hurks H, Rr, Frants, Nelleke Gruis, and Mj, Jager
- Subjects
Adult ,Aged, 80 and over ,Male ,Uveal Neoplasms ,Reverse Transcriptase Polymerase Chain Reaction ,DNA, Neoplasm ,DNA Methylation ,Middle Aged ,Decitabine ,Gene Expression Regulation, Neoplastic ,Azacitidine ,Tumor Cells, Cultured ,Humans ,CpG Islands ,Female ,Gene Silencing ,RNA, Messenger ,Promoter Regions, Genetic ,Melanoma ,Cyclin-Dependent Kinase Inhibitor p16 ,Aged - Abstract
Tumors often display unrestricted cell cycling attributable to a dysfunctional G(1)-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16(INK4a). Although inactivation of p16(INK4a) is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16(INK4a) is reportedly uncommon in uveal melanoma. Here we show that the p16(INK4a) promoter is hypermethylated in 6 of 12 uveal melanoma cell lines and in 7 of 22 primary uveal melanomas analyzed. Five of seven patients with a methylated primary tumor died of metastatic disease compared with 2 of 15 patients with a nonmethylated primary tumor. We also show that all uveal melanoma cell lines with a hypermethylated p16(INK4a) promoter have lost p16(INK4a) expression but have maintained the expression of p14(ARF). Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16(INK4a) and in reexpression of p16(INK4a) mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16(INK4a) promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16(INK4a) expression.
- Published
- 2001