Allelic Imbalances and Homozygous Deletion on 8p23.2 for Stepwise Progression of Hepatocarcinogenesis
Allelic Imbalances and Homozygous Deletion on 8p23.2 for Stepwise Progression of Hepatocarcinogenesis
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DOI：
10.1002/hep.22698
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发表时间：
2009-02-01
期刊：
影响因子：
13.5
通讯作者：
Aburatani, Hiroyuki
中科院分区：
文献类型：
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作者：
Midorikawa, Yutaka;Yamamoto, Shogo;Aburatani, Hiroyuki
早期肝细胞癌（eHCC）起源于慢性肝病的肝细胞，发展为经典型肝细胞癌（HCC）。为了识别多步肝癌发生中的连续遗传变化，我们使用寡核苷酸基因分型50 K阵列分析了分子核型。首先，在eHCC中经常观察到1q21.3-44在1p36.21-36.32和17p13.1-13.3上的杂合性获得和丢失（洛），但在慢性肝病中没有观察到，这表明这种染色体畸变是早期的，可能是肝癌的致病事件。接下来，我们在5例结节中结节外观的HCC中检测了25个与肝癌进展相关的染色体位点，其中内部结节在eHCC病变内发展。以这些染色体区域为自变量，对14例早期肝癌和25例显性肝癌进行决策树分析，提取5q11.1-35.3和8q11.1-24.3的染色体增益和4 q11 -34.3和8p11.21-23.3的洛缺失的组合作为区别性属性，可以递归地对早期肝癌和显性肝癌进行分类。在这四个被鉴定为肝癌发生晚期事件的改变区域中，本研究中分析的32个显性HCC中的两个肿瘤和我们先前研究中36个显性HCC的一组独立样本中的一个在8p23.2上的CSMD 1位点附近具有纯合缺失。CSMD 1 mRNA表达在无8p23.2缺失的HCC中降低，可能是由于其启动子区域CpG岛的高甲基化。结论：1 q的增加和1 p、17 p的洛缺失是早期分子事件，而5 q、8 q的增加和4 q、8 p的洛缺失仅发生于晚期肝癌，推测的抑癌基因CSMD 1的失活可能是肝癌进展的关键事件。（《肝脏学》2009年;49：513-522。）
Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region. Conclusion: 1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer. (HEPATOLOGY 2009;49:513-522.)