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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.

Mutation Inactivation of Nijmegen Breakage Syndrome Gene (NBS1) in Hepatocellular Carcinoma and Intrahepatic Cholangiocarcinoma