Diverse modes of genomic alteration in hepatocellular carcinoma

Jhunjhunwala, Suchit, Jiang, Zhaoshi, Stawiski, Eric W., Gnad, Florian, Liu, Jinfeng, Mayba, Oleg, Du, Pan, Diao, Jingyu, Johnson, Stephanie, Wong, Kwong-Fai, Gao, Zhibo, Li, Yingrui, Wu, Thomas D., Kapadia, Sharookh B., Modrusan, Zora, French, Dorothy M., Luk, John M., Seshagiri, Somasekar and Zhang, Zemin (2014) Diverse modes of genomic alteration in hepatocellular carcinoma. Genome Biology, 15 8: 1-14. doi:10.1186/s13059-014-0436-9


Author Jhunjhunwala, Suchit
Jiang, Zhaoshi
Stawiski, Eric W.
Gnad, Florian
Liu, Jinfeng
Mayba, Oleg
Du, Pan
Diao, Jingyu
Johnson, Stephanie
Wong, Kwong-Fai
Gao, Zhibo
Li, Yingrui
Wu, Thomas D.
Kapadia, Sharookh B.
Modrusan, Zora
French, Dorothy M.
Luk, John M.
Seshagiri, Somasekar
Zhang, Zemin
Title Diverse modes of genomic alteration in hepatocellular carcinoma
Journal name Genome Biology   Check publisher's open access policy
ISSN 1474-760X
Publication date 2014-08-26
Sub-type Article (original research)
DOI 10.1186/s13059-014-0436-9
Open Access Status DOI
Volume 15
Issue 8
Start page 1
End page 14
Total pages 14
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
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.
Keyword Hepatitis-B
Somatic Mutations
Epithelial-Cells
Sequencing Data
Human Cancers
Liver-Cancer
Integration
Dna
Association
Inhibitor
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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