01-06-2007 | Original Paper
Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas
Published in: Journal of Neuro-Oncology | Issue 2/2007
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Aberrant hypermethylation of CpG islands in the promoter region plays a causal role in the inactivation of various key genes involved in the cell cycle regulatory cascade, which could result in a loss of cell cycle control. The aim of the present study was to examine in more detail the prevalence and role of the promoter methylation of genes with a proven involvement in the cell cycle regulation of pituitary adenomas, since their tumorigenesis has not yet been clearly defined. We profiled the CpG island methylation status of a series of well-characterized cell cycle regulation genes: the RB1, p14
ARF
, p15
INK4b
, p16
INK4a
, p21
Waf1/Cip1
, p27
Kip1
, and p73 genes, in 34 pituitary adenomas as determined by a methylation-specific polymerase chain reaction assay. Promoter hypermethylation of the RB1, p14
ARF
, p15
INK4b
, p16
INK4a
, p21
Waf1/Cip1
, p27
Kip1
, and p73 genes was detected in 12 (35%), 2 (6%), 11 (32%), 20 (59%), 1 (3%), 0 (0%), and 4 (12%) of the adenomas, respectively. In total, 88% (30 of 34) of the adenomas displayed methylation of at least one of such cell cycle regulatory genes, especially methylation of the member genes of the RB1 pathway (29 of 34; 85%). Promoter hypermethylation of p15
INK4b
coincided with RB1 and/or p16
INK4a
methylation, whereas RB1 and p16
INK4a
methylations tended to be mutually exclusive (p = 0.0048). Furthermore, promoter hypermethylations of p14
ARF
, p21
Waf1/Cip1
, and p73 (not belonging to the member genes of the RB1 pathway) were also coincident with RB1 and/or p16
INK4a
methylation except in one p73 methylated case. In contrast, none of the clinicopathological features, including the cell proliferation index, was significantly correlated with any particular methylation status. Our results suggested that aberrant hypermethylation of the key cell cycle regulatory genes occurs at a relatively high frequency in pituitary adenomas, especially in RB1 pathway genes with promoter hypermethylation of the p16
INK4a
gene being the most common deregulation. We further obtained evidence to indicate that RB1 and p16
INK4a
methylations tended to be mutually exclusive, but did occasionally coincide with other cell cycle regulation gene methylations.