title: Diverse modes of genomic alteration in hepatocellular carcinoma.
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.
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Eric W
authors.initials: EW
authors.lastname: Stawiski
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: Oleg
authors.initials: O
authors.lastname: Mayba
authors.forename: Pan
authors.initials: P
authors.lastname: Du
authors.forename: Jingyu
authors.initials: J
authors.lastname: Diao
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johnson
authors.forename: Kwong-Fai
authors.initials: KF
authors.lastname: Wong
authors.forename: Zhibo
authors.initials: Z
authors.lastname: Gao
authors.forename: Yingrui
authors.initials: Y
authors.lastname: Li
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Sharookh B
authors.initials: SB
authors.lastname: Kapadia
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Dorothy M
authors.initials: DM
authors.lastname: French
authors.forename: John M
authors.initials: JM
authors.lastname: Luk
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000821:virology; D004252:DNA Mutational Analysis / Q000379:methods*; D018740:Genetic Heterogeneity; D014644:Genetic Variation; D006509:Hepatitis B / Q000235:genetics; D006515:Hepatitis B virus / Q000502:physiology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007797:Laminin / Q000235:genetics*; D008113:Liver Neoplasms / Q000235:genetics* / Q000821:virology; D059645:Mutation Rate; D016019:Survival Analysis
chemical_list: D007797:Laminin; C102645:laminin alpha 2