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[Cancer Research 61, 5303-5306, July 1, 2001]
© 2001 American Association for Cancer Research

Tumor Biology

Promoter Hypermethylation

A Common Cause of Reduced p16INK4a Expression in Uveal Melanoma

Pieter A. van der Velden1, Jessica A. W. Metzelaar-Blok1, Wilma Bergman, H. Monique, H. Hurks, Rune R. Frants, Nelleke A. Gruis2 and Martine J. Jager

Section Human Genetics, Center for Human and Clinical Genetics [P. A. v. d. V., R. R. F., N. A. G.], and Departments of Dermatology [P. A. v. d. V., W. B., N. A. G.], and Ophthalmology [J. A. W. M-B., H. M. H. H., M. J. J.], Leiden University Medical Center, 2333 AL Leiden, the Netherlands

Tumors often display unrestricted cell cycling attributable to a dysfunctional G1-S checkpoint. One of the mechanisms leading to such a defect is the inactivation of the cyclin-dependent kinase inhibitor p16INK4a. Although inactivation of p16INK4a is observed in a wide range of tumors, including cutaneous melanoma, genetic alteration of p16INK4a is reportedly uncommon in uveal melanoma. Here we show that the p16INK4a 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 p16INK4a promoter have lost p16INK4a expression but have maintained the expression of p14ARF. Treatment of uveal melanoma cell lines with 5-aza-2'-deoxycytidine results in demethylation of p16INK4a and in reexpression of p16INK4a mRNA, which is maintained upon withdrawal of the 5-aza-2'-deoxycytidine. In conclusion, p16INK4a promoter methylation appears to be a common event in uveal melanoma and is accompanied by the loss of p16INK4a expression.




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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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Copyright © 2001 by the American Association for Cancer Research.