Ko Eunkyung, Kim Yujin, Kim Sung-Joo, Joh Jae-Won, Song SangYong, Park Cheol-Keun, Park Joobae, Kim Duk-Hwan
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea.
Cancer Epidemiol Biomarkers Prev. 2008 Sep;17(9):2260-7. doi: 10.1158/1055-9965.EPI-08-0236. Epub 2008 Aug 22.
Despite significant advances in the detection and treatment of hepatocellular carcinoma, the prognosis of patients with hepatocellular carcinoma remains very poor, in part due to the high incidence of recurrence. This study was aimed at identifying a prognostic indicator of recurrence in patients with hepatocellular carcinoma. We retrospectively analyzed CpG island hypermethylation of the p14, p15, p16, GSTP1, integrin alpha4, SYK, and CDH1 genes in fresh-frozen tissues from 265 patients with hepatocellular carcinoma using the methylation-specific PCR. The expression levels of p16 and p53 were evaluated by immunohistochemistry. CpG island hypermethylation was detected in 6% for p14, 21% for p15, 67% for p16, 75% for GSTP1, 23% for integrin alpha4, 12% for SYK, and 57% for CDH1. Recurrence was observed in 102 (38%) of the 265 patients. There was no association between the risk for recurrence and hypermethylation of any gene studied. However, p16 methylation was associated with a poor survival after surgery for recurrent stage I to II hepatocellular carcinomas (hazard ratio, 4.05; 95% confidence interval, 1.15-14.20; P = 0.03). In addition, the hazard of failure after recurrence was about 3.80 (95% confidence interval, 1.03-14.20; P = 0.04) times higher in patients with p16 methylation than in those without. Negative expression of p16 at a protein level was also associated with poor survival in recurrent stage I to II hepatocellular carcinomas, but p53 expression did not have a synergistic effect on the poor prognosis. In conclusion, the present study suggests that p16 methylation may be associated with a poor prognosis in recurrent early-stage hepatocellular carcinomas.
尽管肝细胞癌的检测和治疗取得了显著进展，但肝细胞癌患者的预后仍然很差，部分原因是复发率很高。本研究旨在确定肝细胞癌患者复发的预后指标。我们使用甲基化特异性PCR回顾性分析了265例肝细胞癌患者新鲜冷冻组织中p14、p15、p16、GSTP1、整合素α4、SYK和CDH1基因的CpG岛高甲基化情况。通过免疫组织化学评估p16和p53的表达水平。检测到p14的CpG岛高甲基化率为6%，p15为21%，p16为67%，GSTP1为75%，整合素α4为23%，SYK为12%，CDH1为57%。265例患者中有102例（38%）出现复发。所研究的任何基因的高甲基化与复发风险之间均无关联。然而，p16甲基化与I至II期复发性肝细胞癌手术后的不良生存率相关（风险比，4.05；95%置信区间，1.15 - 14.20；P = 0.03）。此外，p16甲基化患者复发后的失败风险比未甲基化患者高约3.80倍（95%置信区间，1.03 - 14.20；P = 0.04）。p16蛋白水平的阴性表达也与I至II期复发性肝细胞癌的不良生存率相关，但p53表达对不良预后没有协同作用。总之，本研究表明p16甲基化可能与早期复发性肝细胞癌的不良预后相关。
