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Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas

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Abstract

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.

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Authors and Affiliations

  1. Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan

    Atsuo Yoshino, Yoichi Katayama, Akiyoshi Ogino, Takao Watanabe, Kazunari Yachi, Takashi Ohta, Chiaki Komine, Takakazu Yokoyama & Takao Fukushima

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  1. Atsuo Yoshino
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  2. Yoichi Katayama
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  3. Akiyoshi Ogino
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Correspondence to Atsuo Yoshino.

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Yoshino, A., Katayama, Y., Ogino, A. et al. Promoter hypermethylation profile of cell cycle regulator genes in pituitary adenomas. J Neurooncol 83, 153–162 (2007). https://doi.org/10.1007/s11060-006-9316-9

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