Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
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肝细胞癌和肝内胆管癌中奈梅亨断裂综合征基因（NBS1）的突变失活
DOI：
10.1371/journal.pone.0082426
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Huang J
中科院分区：
文献类型：
--
作者：
Wang Y;Hong Y;Li M;Long J;Zhao YP;Zhang JX;Li Q;You H;Tong WM;Jia JD;Huang J
奈亨断裂综合征（NBS）伴NBS1种系突变是一种人类常染色体隐性遗传病，其特征是基因组不稳定和癌症易感性增加。NBS1基因编码一种蛋白质NBS1 (p95/Nibrin)，参与DNA双链断裂的加工/修复。肝细胞癌（HCC）是一种复杂的异质性肿瘤，具有多种基因组改变。最近的研究表明，杂合子NBS1小鼠的HCC发病率高于野生型小鼠。本研究的目的是评估NBS1突变是否在人类原发性肝癌的发病机制中发挥作用，包括hbv相关的HCC和肝内胆管癌（ICC）。64例HCC中有6例（9.4%）和18例HCC中有2例（11.1%）发现了8个错义NBS1突变，而89例肝硬化和慢性乙肝对照患者中只发现了1个同义突变。分析鉴定出的NBS1 Mre11结合域突变的功能后果显示，在1例HCC和2例NBS1突变的HCC中，NBS1伴侣Mre11的核定位缺失，这是NBS1缺乏的标志之一。此外，在8个NBS1突变的肿瘤中，有7个在TP53通路中至少存在一个遗传改变，包括TP53突变、MDM2扩增、p14ARF纯合缺失和启动子甲基化，这意味着NBS1破坏和p53失活存在协同作用。我们的研究结果为以DNA修复相关基因NBS1突变失活为特征的原发性肝癌的分子发病机制提供了新的见解。
Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The NBS1 gene codes for a protein, Nbs1(p95/Nibrin), involved in the processing/repair of DNA double-strand breaks. Hepatocellular carcinoma (HCC) is a complex and heterogeneous tumor with several genomic alterations. Recent studies have shown that heterozygous NBS1 mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense NBS1 mutations were identified in six of 64 (9.4%) HCCs and two of 18 (11.1%) ICCs, whereas only one synonymous mutation was found in 89 control cases of cirrhosis and chronic hepatitis B. Analysis of the functional consequences of the identified NBS1 mutations in Mre11-binding domain showed loss of nuclear localization of Nbs1 partner Mre11, one of the hallmarks for Nbs1 deficiency, in one HCC and two ICCs with NBS1 mutations. Moreover, seven of the eight tumors with NBS1 mutations had at least one genetic alteration in the TP53 pathway, including TP53 mutation, MDM2 amplification, p14ARF homozygous deletion and promoter methylation, implying a synergistic effect of Nbs1 disruption and p53 inactivation. Our findings provide novel insight on the molecular pathogenesis of primary liver cancer characterized by mutation inactivation of NBS1, a DNA repair associated gene.
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影响因子：
4.5
作者：
Di, Yuan Ming;Chan, Eli;Zhou, Shu-Feng
通讯作者：
Zhou, Shu-Feng
影响因子：
6.4
作者：
Chrzanowska, KH;Piekutowska-Abramczuk, D;Kowalczyk, J
通讯作者：
Kowalczyk, J
影响因子：
5.2
作者：
Varon, R;Seemanova, E;Reis, A
通讯作者：
Reis, A
影响因子：
11.2
作者：
Ebi, Hiromichi;Matsuo, Keitaro;Takahashi, Takashi
通讯作者：
Takahashi, Takashi
影响因子：
29.4
作者：
Villanueva A;Chiang DY;Newell P;Peix J;Thung S;Alsinet C;Tovar V;Roayaie S;Minguez B;Sole M;Battiston C;Van Laarhoven S;Fiel MI;Di Feo A;Hoshida Y;Yea S;Toffanin S;Ramos A;Martignetti JA;Mazzaferro V;Bruix J;Waxman S;Schwartz M;Meyerson M;Friedman SL;Llovet JM
通讯作者：
Llovet JM