Unique association between global DNA hypomethylation and chromosomal alterations in human hepatocellular carcinoma.
Unique association between global DNA hypomethylation and chromosomal alterations in human hepatocellular carcinoma.
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DOI：
10.1371/journal.pone.0072312
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Goel A
中科院分区：
文献类型：
--
作者：
Nishida N;Kudo M;Nishimura T;Arizumi T;Takita M;Kitai S;Yada N;Hagiwara S;Inoue T;Minami Y;Ueshima K;Sakurai T;Yokomichi N;Nagasaka T;Goel A
整体DNA低甲基化是与染色体不稳定性（CIN）密切相关的癌细胞的特征性特征。然而，在肝癌发生过程中这些特征之间的关联仍不清楚。在此，我们通过分析179例肝细胞癌（HCC）、178例匹配的非肿瘤肝脏和23例正常肝脏组织，确定了低甲基化与CIN之间的关系。使用MethyLight或联合亚硫酸氢盐限制性酶切分析定量了三种不同重复DNA（rDNA）序列的低甲基化和12个CpG位点（包括11个肿瘤抑制基因（TSG）启动子）的高甲基化。通过分析400个微卫星标记，将等位基因缺失分数（FAL）用作CIN的标记。还使用半定量微卫星分析确定每条染色体的增益和损失。研究了rDNA低甲基化和TSG高甲基化与FAL的关系。在HCC组织中观察到的低甲基化显著多于正常肝组织。低甲基化在癌发生过程中的进展在丙型肝炎病毒（HCV）阴性的病例中更为突出，这与我们以前的报告中HCV阳性肿瘤中TSG甲基化水平显着增加相反。肝硬化的缺乏和较高的FAL评分被确定为HCC中rDNA显著低甲基化的独立贡献者。在HCC中经常观察到的染色体改变中，8 p的丢失在肝癌发生的最早阶段是独特的，通过多变量分析与rDNA的低甲基化显著相关（p = 0.0153）。 rDNA低甲基化也与高FAL评分相关，与肿瘤分化无关（p = 0.0011，高分化; p = 0.0089，中/低分化HCC）。 我们的结论是DNA低甲基化是肝癌早期CIN的重要原因，特别是在非硬化性肝脏的背景下。
Global DNA hypomethylation is a characteristic feature of cancer cells that closely associates with chromosomal instability (CIN). However, the association between these characteristics during hepatocarcinogenesis remains unclear. Herein, we determined the relationship between hypomethylation and CIN in human hepatocellular carcinoma (HCC) by analyzing 179 HCCs, 178 matched non-tumor livers and 23 normal liver tissues. Hypomethylation at three different repetitive DNA (rDNA) sequences and hypermethylation of 12 CpG loci, including 11 tumor suppressor gene (TSG) promoters, were quantified using MethyLight or combined bisulfite restriction analysis. Fractional allelic loss (FAL) was used as a marker for CIN, calculated by analyzing 400 microsatellite markers. Gains and losses at each chromosome were also determined using semi-quantitative microsatellite analysis. The associations between rDNA hypomethylation and FAL, as well as between TSG hypermethylation and FAL were investigated. Significantly more hypomethylation was observed in HCC tissues than in normal liver samples. Progression of hypomethylation during carcinogenesis was more prominent in hepatitis C virus (HCV)-negative cases, which was in contrast to our previous reports of significantly increased TSG methylation levels in HCV-positive tumors. Absence of liver cirrhosis and higher FAL scores were identified as independent contributors to significant hypomethylation of rDNA in HCC. Among the chromosomal alterations frequently observed in HCC, loss of 8p, which was unique in the earliest stages of hepatocarcinogenesis, was significantly associated with hypomethylation of rDNA by multivariable analysis (p = 0.0153). rDNA hypomethylation was also associated with a high FAL score regardless of tumor differentiation (p = 0.0011, well-differentiated; p = 0.0089, moderately/poorly-differentiated HCCs). We conclude that DNA hypomethylation is an important cause of CIN in the earliest step of HCC, especially in a background of non-cirrhotic liver.
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影响因子：
3.7
作者：
Nishimura, T;Nishida, N;Nakao, K
通讯作者：
Nakao, K
影响因子：
13.5
作者：
Kojiro, Masamichi;Wanless, Ian R.;Toniakos, Dina
通讯作者：
Toniakos, Dina
影响因子：
56.9
作者：
Gaudet, F;Hodgson, JG;Jaenisch, R
通讯作者：
Jaenisch, R
影响因子：
13.5
作者：
Nishida, Naoshi;Nagasaka, Takeshi;Goell, Ajay
通讯作者：
Goell, Ajay
影响因子：
25.7
作者：
Lachenmayer, Anja;Toffanin, Sara;Cabellos, Laia;Alsinet, Clara;Hoshida, Yujin;Villanueva, Augusto;Minguez, Beatriz;Tsai, Hung-Wen;Ward, Stephen C.;Thung, Swan;Friedman, Scott L.;Llovet, Josep M.
通讯作者：
Llovet, Josep M.