Promoter hypermethylation: a common cause of reduced p16(INK4a) expression in uveal melanoma.
Cancer Res
; 61(13): 5303-6, 2001 Jul 01.
Article
in En
| MEDLINE
| ID: mdl-11431374
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.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Uveal Neoplasms
/
Promoter Regions, Genetic
/
DNA Methylation
/
Cyclin-Dependent Kinase Inhibitor p16
/
Gene Silencing
/
Melanoma
Limits:
Adult
/
Aged
/
Aged80
/
Female
/
Humans
/
Male
/
Middle aged
Language:
En
Journal:
Cancer Res
Year:
2001
Type:
Article
Affiliation country:
Netherlands