Influence of methylated p15INK4b and p16INK4a genes on clinicopathological features in colorectal cancer
Influence of methylated p15INK4b and p16INK4a genes on clinicopathological features in colorectal cancer
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DOI：
10.1111/j.1440-1746.2006.04137.x
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发表时间：
2006-08-01
影响因子：
4.1
通讯作者：
Munakata, Akihiro
中科院分区：
文献类型：
--
作者：
Ishiguro, Atsushi;Takahata, Takenori;Munakata, Akihiro
背景与目的：启动子甲基化导致的基因沉默在大肠癌的发生发展中受到关注。p16（INK 4a）基因的甲基化已在原发性结直肠癌中发现。尽管p15（INK 4 b）基因在氨基酸序列上与p16（INK 4a）基因显示出高度同源性，但尚未充分研究p15（INK 4 b）的甲基化。我们研究了结直肠癌患者中p15（INK 4 b）甲基化状态，以验证p15（INK 4 b）甲基化与p16（INK 4a）甲基化之间的相关性。研究方法：从88例（男47例，女41例，年龄29-83岁）手术切除的原发性结直肠癌组织和相应的邻近正常结肠粘膜中获得DNA样品。甲基化特异性聚合酶链反应用于分析亚硫酸氢盐修饰后p15（INK 4 b）和p16（INK 4a）甲基化状态。结果：p15（INK 4 b）和p16（INK 4a）基因甲基化分别在23例（26.1%）和20例（22.7%）结直肠癌中检出。p15（INK 4 b）甲基化与任何临床病理特征无关。p15（INK 4 b）基因甲基化在肿瘤组织中的表达显著高于正常粘膜（P < 0.001）。逆转录-聚合酶链反应（RT-PCR）显示p15（INK 4 b）甲基化降低mRNA表达。Kaplan-Meier分析显示，p15（INK 4 b）基因甲基化与非甲基化患者的生存率有显著性差异（P = 0.018）。结论：p15（INK 4 b）基因甲基化与p16（INK 4a）基因甲基化一样参与了结直肠癌的发生过程，可作为结直肠癌早期的预后指标。
Background and Aim: Genetic silencing by promoter methylation has attracted attention in the carcinogenesis of colorectal cancer. Methylation of the p16(INK4a) gene has been found in primary colorectal cancer. Although the p15(INK4b) gene displays high homology to the p16(INK4a) gene in the amino acid sequence, methylation of p15(INK4b) has not been fully studied. We investigated p15(INK4b) methylation status in patients with colorectal cancer to verify the association between the methylation of p15(INK4b) and clinicopathological features compared with p16(INK4a.)Methods: DNA samples from the tissues of primary colorectal cancer and corresponding adjacent normal colon mucosa were obtained from surgical resections of 88 patients (47 males and 41 females, aged 29-83 years). Methylation-specific polymerase chain reaction was used to analyze p15(INK4b) and p16(INK4a) methylation status after bisulfite modification. Cumulative survival rates (mean follow-up period: 53.2 months) were calculated by the Kaplan-Meier analysis.Results: Methylations of p15(INK4b) and p16(INK4a) genes were detected in 23 (26.1%) and 20 (22.7%) colorectal cancers, respectively. Methylation of p15(INK4b) was not associated with any clinicopathological features. Compared with normal mucosa, the methylation of p15(INK4b) was more prominent in tumor tissue (P < 0.001). Reverse transcription-polymerase chain reaction (RT-PCR) revealed that p15(INK4b) methylaton decreased mRNA expression. Kaplan-Meier analysis showed that patients with stage I-II had a significant difference in survival rate between those with and without methylated p15(INK4b) (P = 0.018).Conclusions: Our results suggest that methylation of the p15(INK4b) gene contributes to the process of carcinogenesis in colorectal cancer as well as p16(INK4a) and is useful as a prognostic factor in the early stage.