Herath Nirmitha I, Purdie David M, Kew Michael C, Smith Jeffery L, Young Joanne, Leggett Barbara A, MacDonald Graeme A
Leukemia Foundation of Queensland, The Queensland Institute of Medical Research, Brisbane 4029, QLD, Australia.
Int J Oncol. 2009 Nov;35(5):1081-9. doi: 10.3892/ijo_00000423.
There is significant regional variation in the etiologic agents responsible for hepatocellular carcinoma (HCC), which influences the genetic and epigenetic mechanisms of malignant transformation. The aim of the present study was to investigate the prevalence of allelic imbalance (AI) and CpG island methylation in HCCs from Australia and South Africa. Genomic DNA was extracted from malignant and non-malignant liver from 37 Australian and 24 South African HCCs and histologically normal liver from 20 transplant donors. AI was examined at 1p, 4p, 4q, 8p, 9p, 13q, 16q and 17p, using 23 microsatellite markers. Methylation status of p14, p16, p15, RIZ1, E-cadherin and O6-MGMT was examined using methylation specific PCR, while MINTs 1, 2, 12, 25 and 31 were assessed using combined bisulfite restriction analysis. The highest prevalence of AI was observed at 9p (69%) and 17p (52%). AI was significantly higher in South African HCCs (p<0.05). The prevalence of promoter methylation of the six genes was significantly higher in Australian cases in both malignant and non-malignant liver tissue (p<0.05). MINT assays revealed an increasing degree of CpG island methylation in the progression of hepatocarcinogenesis which was significant for MINTs 1, 12 and 31 (p<0.05). MINT methylation was more prominent in Australian HCCs. These data indicate that methylation is an early event preceding malignant transformation. Methylation was more and AI less prevalent in Australian than South African HCCs. These data suggest that there are different mechanisms of malignant transformation in HCCs from Australia and South Africa.
肝细胞癌（HCC）的致病因素存在显著的地区差异，这影响了恶性转化的遗传和表观遗传机制。本研究的目的是调查澳大利亚和南非HCC中基因座不平衡（AI）和CpG岛甲基化的发生率。从37例澳大利亚和24例南非HCC的恶性和非恶性肝脏以及20例移植供体的组织学正常肝脏中提取基因组DNA。使用23个微卫星标记物在1p、4p、4q、8p、9p、13q、16q和17p处检测AI。使用甲基化特异性PCR检测p14、p16、p15、RIZ1、E-钙黏蛋白和O6-甲基鸟嘌呤-DNA甲基转移酶（O6-MGMT）的甲基化状态，同时使用亚硫酸氢盐联合限制性分析评估MINT1、2、12、25和31。在9p（69%）和17p（52%）处观察到AI的最高发生率。南非HCC中的AI显著更高（p<0.05）。在澳大利亚病例的恶性和非恶性肝组织中，六个基因的启动子甲基化发生率均显著更高（p<0.05）。MINT分析显示，在肝癌发生过程中CpG岛甲基化程度增加，这在MINT1、12和31中具有显著性（p<0.05）。MINT甲基化在澳大利亚HCC中更为突出。这些数据表明甲基化是恶性转化之前的早期事件。澳大利亚HCC中的甲基化比AI更普遍，而南非HCC则相反。这些数据表明，澳大利亚和南非HCC的恶性转化机制不同。
