Article

Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Center for Genomic Medicine, RIKEN, Yokohama, Japan.
Nature Genetics (Impact Factor: 29.35). 05/2012; 44(7):760-4. DOI: 10.1038/ng.2291
Source: PubMed

ABSTRACT

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ∼50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.

Download full-text

Full-text

Available from: Akihiro Fujimoto, Oct 29, 2014
  • Source
    • "A strict interpretation of this requirement would limit tumour antigens to antigens resulting from somatic mutations, chromosomal translocations resulting in neo-antigens, or viral-derived antigens. However, exome sequencing has recently shown that somatic mutation patterns in HCC are strongly variable between individual patients and therefore not suitable for design of off-the-shelf therapeutic vaccines (Fujimoto et al, 2012). The most promising alternative tumour antigens are cancer-testis antigens, which are exclusively expressed in germ cells but not in other normal tissues (Hofmann et al, 2008), and oncofetal antigens, expressed primarily during embryogenesis but not broadly in adult humans (AFP, Glypican-3). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Identification of tumour antigens is crucial for the development of vaccination strategies against hepatocellular carcinoma (HCC). Most studies come from eastern-Asia, where hepatitis-B is the main cause of HCC. However, tumour antigen expression is poorly studied in low-endemic, western areas where the aetiology of HCC differs. We constructed tissue microarrays from resected HCC tissue of 133 patients. Expression of a comprehensive panel of cancer-testis (MAGE-A1, MAGE-A3/4, MAGE-A10, MAGE-C1, MAGE-C2, NY-ESO-1, SSX-2, sperm protein 17), onco-fetal (AFP, Glypican-3) and overexpressed tumour antigens (Annexin-A2, Wilms tumor-1, Survivin, Midkine, MUC-1) was determined by immunohistochemistry. A higher prevalence of MAGE antigens was observed in patients with hepatitis-B. Patients with expression of more tumour antigens in general had better HCC-specific survival (P=0.022). The four tumour antigens with high expression in HCC and no, or weak, expression in surrounding tumour-free-liver tissue, were Annexin-A2, GPC-3, MAGE-C1 and MAGE-C2, expressed in 90, 39, 17 and 20% of HCCs, respectively. Ninety-five percent of HCCs expressed at least one of these four tumour antigens. Interestingly, GPC-3 was associated with SALL-4 expression (P=0.001), an oncofetal transcription factor highly expressed in embryonal stem cells. SALL-4 and GPC-3 expression levels were correlated with vascular invasion, poor differentiation and higher AFP levels before surgery. Moreover, patients who co-expressed higher levels of both GPC-3 and SALL-4 had worse HCC-specific survival (P=0.018). We describe a panel of four tumour antigens with excellent coverage and good tumour specificity in a western area, low-endemic for hepatitis-B. The association between GPC-3 and SALL-4 is a novel finding and suggests that GPC-3 targeting may specifically attack the tumour stem-cell compartment.
    Full-text · Article · Jun 2015 · British Journal of Cancer
  • Source
    • "ARID1A, which encodes a key component of the SWI/SNF chromatin remodeling complex, was also found to be mutated in 13% of HCC specimens isolated from HBV patients in a separate study (Huang et al., 2012). If the expression of these chromatin regulators in HCC cell lines that expressed the wild-type genes were suppressed by siRNA, cell proliferation, invasion and migration were enhanced, supporting the role of these loss-of-function mutations in the development of HCC (Fujimoto et al., 2012; Huang et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). Its chronic infection can lead to chronic liver inflammation and the accumulation of genetic alterations to result in the oncogenic transformation of hepatocytes. HBV can also sensitize hepatocytes to oncogenic transformation by causing genetic and epigenetic changes of the host chromosomes. HBV DNA can insert into host chromosomes and recent large-scale whole-genome sequencing studies revealed recurrent HBV DNA integrations sites that may play important roles in the initiation of hepatocellular carcinogenesis. HBV can also cause epigenetic changes by altering the methylation status of cellular DNA, the post-translational modification of histones, and the expression of microRNAs. These changes can also lead to the eventual hepatocellular transformation. These recent findings on the genetic and epigenetic alterations of the host chromosomes induced by HBV opened a new avenue for the development of novel diagnosis and treatments for HBV-induced HCC.
    Full-text · Article · Apr 2015 · Virologica Sinica
  • Source
    • "ARID1A, which encodes a key component of the SWI/SNF chromatin remodeling complex, was also found to be mutated in 13% of HCC specimens isolated from HBV patients in a separate study (Huang et al., 2012). If the expression of these chromatin regulators in HCC cell lines that expressed the wild-type genes were suppressed by siRNA, cell proliferation, invasion and migration were enhanced, supporting the role of these loss-of-function mutations in the development of HCC (Fujimoto et al., 2012; Huang et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis B virus (HBV) is a hepatotropic virus and one of the most important human pathogens. It can cause acute and chronic hepatitis. Chronic HBV infection can also lead to liver cirrhosis and the development of hepatocellular carcinoma (HCC). HBV may induce HCC indirectly via the induction of chronic liver inflammation, which can cause oxidative stress and repeated liver injury and regeneration to lead to the accumulation of genetic alterations and eventually the oncogenic transformation of hepatocytes. HBV may also directly induce hepatocellular transformation by causing genetic and epigenetic changes of its host cells. HBV DNA can insert into host chromosomes and recent large-scale whole-genome sequencing studies revealed recurrent HBV DNA integrations sites that may play important roles in the initiation of hepatocellular carcinogenesis. HBV can also elicit epigenetic changes by altering the methylation status of cellular DNA, the post-translational modification of histones and the expression of noncoding RNAs. These epigenetic changes can also have a profound impact on the eventual hepatocellular transformation. Understanding the genetic and epigenetic alterations induced by HBV will facilitate the understanding of the mechanisms of HBV-induced hepatocellular carcinogenesis and improve the diagnosis and treatments for HBV-associated HCC.
    Full-text · Article · Apr 2015 · Virologica Sinica
Show more