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Aug 8, 2011

Investigators Identify Inactivating Mutations in Tumor Suppressor Gene ARID2

  • Researchers have found inactivating mutations in the ARID2 gene in 18.2% of patients with HCV-associated hepatocellular carcinoma (HCV-associated HCC).  The international team, led by Michael S. Torbenson, M.D., and Kenneth W. Kinzler, M.D., at the Johns Hopkins University School of Medicine, initially identified mutations in ARID2 in tumor samples from 10 HCV-associated HCC patients. They subsequently confirmed their findings in an additional 23 patients.

    Writing in Nature Genetics, the researchers say data from their exon-sequencing studies suggest all the identified mutations were predicted to inactivate the encoded ARID2 protein, “unequivocally establishing ARID2 as an HCC tumor suppressor gene.” Their results are detailed a paper titled “Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma.”

    The five-year survival rate for individuals with liver cancer is 11.7%, making it one of the most lethal forms of neoplasia, the researchers write. Epidemiologic studies have in addition conclusively linked HBV and HCV infections with development of the disease. To further investigate the genetic basis of HCC, the Johns Hopkins-led team sequenced about 18,000 protein-coding genes in the tumor and normal tissue samples taken from 10 patients with HCV-associated HCC.

    Five genes were found to be somatically mutated in more than one tumor: CTNNB1 was mutated in four tumors, TP53 in three tumors, and ARID2, DMXL1, and NLRP1 in two tumors. Evaluating all coding exons of these five genes in another 23 HCV-associated HCCs found that CTNNB1, TP53, ARID2, DMXL1, and NLRP1 were mutated in 8 (24.2%), 4 (12.1%), 6 (18.2%), 2 (6.1%), and 2 (6.1%) of the total 33 HCCs, respectively.

    Of the three most commonly mutated genes, CTNNB1 and TP53 have been previously observed in HCC, but ARID2 hasn’t. The gene is a subunit of the polybromo- and BRG1-associated actor (PBAF) chromatin remodeling complex, which facilitates ligand-dependent transcriptional activation by nuclear receptors.

    When the team compared the frequency of ARID2 mutations in additional HBV-associated HCC tumors and HCV-associated HCC tumors, they found that while the gene was altered in 14% of HCV-associated HCC cancers, it was only mutated in 2% of HBV-associated malignancies.

    Moreover, ARID2 mutations were correlated with CTNNB1 mutations but tended to be mutually exclusive with TP53 mutations: of nine HCC samples with ARID2 mutations, and six contained CTNNB1 mutations, but none contained TP53 mutations.

    Clues as to the impact of ARID2 mutation come from previous research, the authors state. Functional studies have shown that suppression of ARID2 by small interfering RNA reduced both basal and interferon-α–induced IFITM1 (interferon-induced transmembrane protein 1) expression. Meanwhile, it has also been suggested that subverting the function of interferon-α–induced Jak-STAT signaling is important for the lifelong persistence of HCV infection.

    “Thus we hypothesize that the inactivating mutations in ARID2 could repress interferon-α–induced Jak-STAT signaling and thereby provide a selective advantage for chronic HCV propagation during HCC development,” the authors conclude. 


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