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.
Highlights
Hepatocellular carcinoma (HCC) is a heterogeneous disease with high mortality rate
We have previously shown that hepatitis B virus (HBV) DNA frequently integrates into the human genome, causing diverse changes such as DNA copy number variation, chimeric viral-human transcript fusions, and transcriptional activation [3]
Aside from individual genes mutated in HCC, we examine the diverse modes of genomic alteration in this heterogeneous disease, delineating both conventional mutations and virus-associated changes that contribute to liver oncogenesis
Summary
Hepatocellular 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. Hepatitis B virus (HBV) integrations into the human genome have been associated with HCC. Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death, with a poor 5-year survival rate of less than 10% [1]. Several emerging themes were revealed by recent genomic studies [3,4,5,6], including recurrent mutations in TP53, Wnt-signaling components CTNNB1 and AXIN1, and structural variations, and virus-mediated mutations. We have previously shown that HBV DNA frequently integrates into the human genome, causing diverse changes such as DNA copy number variation, chimeric viral-human transcript fusions, and transcriptional activation [3]. Given the disruptive nature of HBV integration, it is pertinent to study all modes of genomic changes in the same context
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