Diverse modes of genomic alteration in hepatocellular carcinoma

Abstract

BackgroundHepatocellular carcinoma (HCC) is a heterogeneous disease with high mortality rate. Recent genomic studies have identified TP53, AXIN1, and CTNNB1 as the most frequently mutated genes. Lower frequency mutations have been reported in ARID1A, ARID2 and JAK1. In addition, hepatitis B virus (HBV) integrations into the human genome have been associated with HCC.ResultsHere, we deep-sequence 42 HCC patients with a combination of whole genome, exome and transcriptome sequencing to identify the mutational landscape of HCC using a reasonably large discovery cohort. We find frequent mutations in TP53, CTNNB1 and AXIN1, and rare but likely functional mutations in BAP1 and IDH1. Besides frequent hepatitis B virus integrations at TERT, we identify translocations at the boundaries of TERT. A novel deletion is identified in CTNNB1 in a region that is heavily mutated in multiple cancers. We also find multiple high-allelic frequency mutations in the extracellular matrix protein LAMA2. Lower expression levels of LAMA2 correlate with a proliferative signature, and predict poor survival and higher chance of cancer recurrence in HCC patients, suggesting an important role of the extracellular matrix and cell adhesion in tumor progression of a subgroup of HCC patients.ConclusionsThe heterogeneous disease of HCC features diverse modes of genomic alteration. In addition to common point mutations, structural variations and methylation changes, there are several virus-associated changes, including gene disruption or activation, formation of chimeric viral-human transcripts, and DNA copy number changes. Such a multitude of genomic events likely contributes to the heterogeneous nature of HCC.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-014-0436-9) contains supplementary material, which is available to authorized users.

Hepatocyte Factor JMJD5 Regulates Hepatitis B Virus Replication through Interaction with HBx

“…For example, HBx has been shown to directly interact with the tumor suppressor gene p53 and to inactivate p53-mediated transcription (25). Although HBx has been shown to activate RAS (7), the incidence of HBx-induced HCC in mice was accelerated by the knockdown of p53 (71), suggesting that inhibition of p53 by HBx is not sufficient to induce liver cancer in mice. In addition, cooperation with NRAS was not needed for HBx-induced liver cancer in mice (71).…”

“…Although HBx has been shown to activate RAS (7), the incidence of HBx-induced HCC in mice was accelerated by the knockdown of p53 (71), suggesting that inhibition of p53 by HBx is not sufficient to induce liver cancer in mice. In addition, cooperation with NRAS was not needed for HBx-induced liver cancer in mice (71). Further studies are needed to clarify the molecular mechanisms by which HBx promotes the development of HCC and the infection with HBV.…”

Atg5 siRNA inhibits autophagy and enhances norcantharidin-induced apoptosis in hepatocellular carcinoma

“…Because of the complex mechanisms of HCC, effective therapies toward HCC have not significantly improved (1,2). As a heterogeneous tumor, HCC involves multiple pathways and molecular alterations (14). With medical technology advances, there are increasing number of new treatments towards HCC, including surgical resection, liver transplantation and chemotherapy or immuno-biological cancer therapy.…”

A human-specific switch of alternatively splicedAFMIDisoforms contributes toTP53mutations and tumor recurrence in hepatocellular carcinoma

“…S1). We started with an RNA-Seq dataset of 11 primary HCCs and matched adjacent normal liver (ANL) tissues from a recent study (Jhunjhunwala et al 2014). Also, we analyzed 136 non-HCC liver samples from the Genotype-Tissue Expression (GTEx) database, and 16 liver-cancer cell lines (Consortium 2015;Klijn et al 2015).…”