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

<div><p>Nijmegen breakage syndrome (NBS) with <i>NBS1</i> germ-line mutation is a human autosomal recessive disease characterized by genomic instability and enhanced cancer predisposition. The <i>NBS1</i> 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 <i>NBS1</i> mice exhibited a higher incidence of HCC than did wild-type mice. The objective of the present study is to assess whether <i>NBS1</i> mutations play a role in the pathogenesis of human primary liver cancer, including HBV-associated HCC and intrahepatic cholangiocarcinoma (ICC). Eight missense <i>NBS1</i> 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 <i>NBS1</i> 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 <i>NBS1</i> mutations. Moreover, seven of the eight tumors with <i>NBS1</i> mutations had at least one genetic alteration in the <i>TP53</i> pathway, including <i>TP53</i> mutation, <i>MDM2</i> amplification, <i>p14ARF</i> 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 <i>NBS1</i>, a DNA repair associated gene.</p>