title: Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
abstract: 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.
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Hong
authors.affiliation: Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Man
authors.initials: M
authors.lastname: Li
authors.affiliation: Minimally Invasive Hepatobiliary Cancer Center, Beijing You-An Hospital, Capital Medical University, Beijing, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Long
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhao
authors.affiliation: Department of Hepatology, Tianjin Infectious Disease Specialty Hospital, Tianjin, China.
authors.forename: Jun-Xia
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Department of Preventive Medicine, Mt. Sinai School of Medicine, New York, New York, United States of America.
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: You
authors.affiliation: Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Tong
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Ji-Dong
authors.initials: JD
authors.lastname: Jia
authors.affiliation: Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001483:Base Sequence; D001650:Bile Duct Neoplasms / Q000235:genetics* / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000473:pathology; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D019694:Hepatitis B, Chronic / Q000235:genetics; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D000076228:MRE11 Homologue Protein; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D000076228:MRE11 Homologue Protein