Tumor p16INK4 gene expression and prognosis in colorectal cancer
Tumor p16INK4 gene expression and prognosis in colorectal cancer
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DOI：
10.3892/or.2018.6884
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发表时间：
2019-02-01
期刊：
影响因子：
4.2
通讯作者：
Minamoto, Toshinari
中科院分区：
文献类型：
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作者：
Kitamura, Hirotaka;Takemura, Hirofumi;Minamoto, Toshinari
肿瘤抑制基因p16（INK 4）（p16）启动子的高甲基化与结直肠癌（CRC）的预后不良相关。本研究旨在探讨p16 mRNA表达与其启动子甲基化是否相关，以及是否影响结直肠癌患者的预后。从101例手术切除的肿瘤标本中提取DNA和RNA。使用MethyLight测定法定量p16甲基化的甲基化参考（PMR）的百分比，并使用逆转录聚合酶链反应测定p16 mRNA的表达。采用Kaplan-Meier分析和考克斯比例风险回归评价p16甲基化或mRNA表达与患者生存率之间的关系。p16基因甲基化检出率为66.3%（67/67），中位PMR值为0.344（0.00-468.6）。以PMR值为4为临界值，在18例（17.8%）中观察到p16高甲基化。p16甲基化水平与患者预后无显著相关性。正如预期的那样，在p16甲基化和mRNA表达之间观察到显著的负相关（P=0.034）。在83例p16甲基化水平低的病例中，p16 mRNA表达水平高的患者预后明显较差（P=0.026）。多因素分析显示p16 mRNA表达是影响预后的独立因素（P=0.011）。这些结果表明，肿瘤中p16 mRNA的高水平表达与结直肠癌患者的预后不良之间存在矛盾的关系。
Hypermethylation of the tumor suppressor gene p16(INK4) (p16) promoter is associated with worse prognosis in colorectal cancer (CRC). In the present study, it was investigated whether p16 mRNA expression correlates with the methylation of its promoter, and whether it influences prognosis in patients with CRC. DNA and RNA were extracted from 101 resected tumor specimens. A MethyLight assay was used to quantify p16 methylation in terms of percentage of methylated reference (PMR), and the expression of p16 mRNA was measured using reverse transcription-polymerase chain reaction. Associations between p16 methylation or mRNA expression and patient survival were evaluated using Kaplan-Meier analysis and Cox proportional hazards regression. p16 methylation was detected in 67 cases (66.3%) and the median PMR value was 0.344 (range, 0.00-468.6). Using a cut-off PMR value of 4, high p16 methylation was observed in 18 cases (17.8%). No significant association was observed between p16 methylation level and patient prognosis. As expected, a significant inverse association was observed between p16 methylation and mRNA expression (P=0.034). Amongst the 83 cases with low p16 methylation, a significantly worse outcome was identified in patients expressing high p16 mRNA expression levels (P=0.026). Multivariate analysis identified that p16 mRNA expression was an independent prognostic factor for worse survival (P=0.011). These results suggested a paradoxical association between high levels of p16 mRNA expression in the tumor and worse prognosis in patients with CRC.