Diverse modes of genomic alteration in hepatocellular carcinoma
Genome Biology
Diverse modes of genomic alteration in hepatocellular carcinoma
Suchit Jhunjhunwala 0 7
Zhaoshi Jiang 0
Eric W Stawiski 0 2
Florian Gnad 0
Jinfeng Liu 0
Oleg Mayba 0
Pan Du 0
Jingyu Diao 1
Stephanie Johnson 6
Kwong-Fai Wong 5
Zhibo Gao 4
Yingrui Li 4
Thomas D Wu 0
Sharookh B Kapadia 1
Zora Modrusan 2
Dorothy M French 6
John M Luk 3 5 8
Somasekar Seshagiri 2
Zemin Zhang 0 7
0 Department of Bioinformatics and Computational Biology, Genentech Inc. , South San Francisco, CA 94080 , USA
1 Department of Infectious diseases, Genentech Inc. , South San Francisco, CA 94080 , USA
2 Department of Molecular Biology, Genentech Inc. , South San Francisco, CA 94080 , USA
3 Department of Pharmacology, National University of Singapore , Singapore 117597 , Singapore
4 BGI-Shenzhen , Shenzhen 518083 , China
5 Department of Surgery, University of Hong Kong , Pokfulam , Hong Kong
6 Department of Pathology, Genentech Inc. , South San Francisco, CA 94080 , USA
7 STAR , 61 Biopolis Drive , Singapore 138673 , Singapore
8 Institute of Molecular and Cell Biology , A
Background: 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. 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. Results: Here, 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. Conclusions: The 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.
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Background
Hepatocellular carcinoma (HCC) is the third leading cause
of cancer-related death, with a poor 5-year survival rate of
less than 10% [1]. While more than 600,000 new cases are
diagnosed annually, there is no effective targeted therapy.
HCC is highly heterogeneous and associated with various
etiological factors, including hepatitis B virus (HBV) or
hepatitis C virus (HCV) infection, alcohol consumption
and exposure to aflatoxin and possibly vinyl chloride [2].
Several emerging themes were revealed by recent genomic
studies [3-6], including recurrent mutations in TP53,
Wnt-signaling components CTNNB1 and AXIN1, and
chromatin regulators like ARID1A and ARID2, as well
as HBV integration near TERT, CCNE1 and MLL4. The
frequently altered genes discovered by these studies
have differed, however, possibly due to small discovery
panels (up to 25 patients) and the inherent
heterogeneity of HCC due to several associated etiological factors.
For example, activating mutations in CTNNB1 are
mutually exclusive with HBV infection [6] and hence would
not be prominent in a cohort enriched for HBV-infected
patients. Therefore, it might not be surprising that
different studies have identified different genes that are
mutated in the population at low frequency, like ARID2,
ARID1A and JAK1. Another difficulty in constructing
the complete mutational landscape in HCC is the focused
nature of most previous studies, since it is not common for
a single study to comprehensively examine multiple types
of genomic changes that include point mutations, deletions,
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.
In this study, we analyzed a panel of 42 HCC patients
with a combination of whole-genome, exome and
transcriptome sequencing. We identified multiple high-allelic
frequency mutations in LAMA2. LAMA2 encodes the
subunit of laminin, the major c (...truncated)