Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma

PLoS One. 2013 Dec 13;8(12):e82426. doi: 10.1371/journal.pone.0082426. eCollection 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Base Sequence
  • Bile Duct Neoplasms / genetics*
  • Bile Duct Neoplasms / pathology
  • Bile Ducts, Intrahepatic / pathology
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics*
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cholangiocarcinoma / genetics*
  • Cholangiocarcinoma / pathology
  • DNA Mutational Analysis
  • DNA-Binding Proteins / metabolism
  • Female
  • Gene Silencing*
  • Hepatitis B, Chronic / genetics
  • Humans
  • Liver Cirrhosis / genetics
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • MRE11 Homologue Protein
  • Male
  • Mice
  • Middle Aged
  • Molecular Sequence Data
  • Mutation / genetics*
  • Mutation Rate
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics*
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein Transport
  • Tumor Suppressor Protein p53 / genetics

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nijmegen breakage syndrome 1 protein, mouse
  • Nuclear Proteins
  • Tumor Suppressor Protein p53
  • MRE11 Homologue Protein

Associated data

  • GENBANK/JN390965
  • GENBANK/KF147842
  • GENBANK/KF147843
  • GENBANK/KF147844
  • GENBANK/KF147845
  • GENBANK/KF147846
  • GENBANK/KF147847
  • GENBANK/KF147848

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (81071973), Beijing Municipal Natural Science Foundation (7132058) and a grant from Beijing Friendship Hospital, Capital Medical University (200936). Dr Wei-Min Tong was supported in part by National Natural Science Foundation of China (30970602) and 111 project. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.