PloS one, 2013-12, Vol.8 (12), p.e82426
2013
Details
- Autor(en) / Beteiligte
- Titel
- Mutation inactivation of Nijmegen breakage syndrome gene (NBS1) in hepatocellular carcinoma and intrahepatic cholangiocarcinoma
- Ist Teil von
- PloS one, 2013-12, Vol.8 (12), p.e82426
- Ort / Verlag
- United States: Public Library of Science
- Erscheinungsjahr
- 2013
- Link zum Volltext
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1932-6203eISSN: 1932-6203DOI: 10.1371/journal.pone.0082426Titel-ID: cdi_plos_journals_1468934708
- Format
- –
- Schlagworte
- Adult, Aged, Animals, Base Sequence, Bile Duct Neoplasms - genetics, Bile Duct Neoplasms - pathology, Bile Ducts, Intrahepatic - pathology, Biliary tract cancer, Breakage, Breast cancer, Cancer, Cancer genetics, Carcinoma, Hepatocellular - genetics, Carcinoma, Hepatocellular - pathology, Cell cycle, Cell Cycle Proteins - chemistry, Cell Cycle Proteins - genetics, Cell Line, Tumor, Cell Nucleus - metabolism, Cholangiocarcinoma, Cholangiocarcinoma - genetics, Cholangiocarcinoma - pathology, Cirrhosis, Deactivation, Deoxyribonucleic acid, DNA, DNA damage, DNA methylation, DNA Mutational Analysis, DNA repair, DNA-Binding Proteins - metabolism, Ethics, Female, Gene deletion, Gene Silencing, Genes, Genetic aspects, Genomes, Genomic instability, Hepatitis, Hepatitis B, Hepatitis B, Chronic - genetics, Hepatocellular carcinoma, Hepatology, Hepatoma, Hospitals, Humans, Inactivation, Infections, Infectious diseases, Ionizing radiation, Leukemia, Liver, Liver cancer, Liver cirrhosis, Liver Cirrhosis - genetics, Liver Neoplasms - genetics, Liver Neoplasms - pathology, Localization, Lymphoma, Male, MDM2 protein, Methylation, Mice, Middle Aged, Molecular Sequence Data, MRE11 Homologue Protein, MRE11 protein, Mutation, Mutation - genetics, Mutation Rate, NBS1 gene, Nijmegen breakage syndrome, Nuclear Proteins - chemistry, Nuclear Proteins - genetics, p53 Protein, Pathogenesis, Preventive medicine, Protein Binding, Protein Structure, Tertiary, Protein Transport, Repair, Rodents, Stability, Synergistic effect, Tumor proteins, Tumor Suppressor Protein p53 - genetics, Tumors