Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status.
Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status.
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发表时间：
2000
期刊：
影响因子：
11.2
通讯作者：
M. Esteller;S. Tórtola;Minoru Toyota;G. Capellá;M. Peinado;S. Baylin;James G. Herman
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文献类型：
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作者：
M. Esteller;S. Tórtola;Minoru Toyota;G. Capellá;M. Peinado;S. Baylin;James G. Herman
INK4a/ARF 基因座编码两种细胞周期调节蛋白 p16INK4a 和 p14ARF，它们共享一个使用不同阅读框的外显子。 p14ARF 拮抗 MDM2 依赖性 p53 降解。然而，在原发性肿瘤中尚未发现 p14ARF 点突变不会改变 p16INK4a。我们报告说，p14ARF 在几种结直肠细胞系中表观遗传失活，并且通过去甲基化剂处理可以恢复其表达。在原发性结直肠癌中，在 110 个肿瘤中的 31 个 (28%) 中发现了 p14ARF 启动子高甲基化，在 41 个结直肠腺瘤中的 13 个 (32%) 中观察到了 p14ARF 启动子高甲基化，但在任何正常组织中都不存在。在 p14ARF 甲基化的 31 个癌中，有 16 个（52%）中，p14ARF 甲基化出现在相邻的未甲基化 p16INK4a 启动子的背景中。尽管与携带 p53 突变的肿瘤相比，野生型 p53 肿瘤中 p14ARF 高甲基化程度稍高 [55 个肿瘤中的 19 个 (34%) 对比 55 个肿瘤中的 12 个 (22%)]，但这种差异并未达到统计学显着性。 p14ARF 异常甲基化与 K-ras 突变的存在无关。我们的结果表明，p14ARF 启动子高甲基化在结直肠癌中很常见，并且独立于 p16INK4a 甲基化状态而发生，仅与 p53 突变状态有一定关系。
The INK4a/ARF locus encodes two cell cycle-regulatory proteins, p16INK4a andp14ARF, which share an exon using different reading frames. p14ARF antagonizes MDM2-dependent p53 degradation. However, no point mutations in p14ARF not altering p16INK4a have been described in primary tumors. We report that p14ARF is epigenetically inactivated in several colorectal cell lines, and its expression is restored by treatment with demethylating agents. In primary colorectal carcinomas, p14ARF promoter hypermethylation was found in 31 of 110 (28%) of the tumors and observed in 13 of 41 (32%) colorectal adenomas but was not present in any normal tissues. p14ARF methylation appears in the context of an adjacent unmethylated p16INK4a promoter in 16 of 31 (52%) of the carcinomas methylated at p14ARF. Although p14ARF hypermethylation was slightly overrepresented in tumors with wild-type p53 compared to tumors harboring p53 mutations [19 of 55 (34%) versus 12 of 55 (22%)], this difference did not reach statistical significance. p14ARF aberrant methylation was not related to the presence of K-ras mutations. Our results demonstrate that p14ARF promoter hypermethylation is frequent in colorectal cancer and occurs independently of the p16INK4a methylation status and only marginally in relation to the p53 mutational status.