title: Etiology-dependent molecular mechanisms in human hepatocarcinogenesis.
abstract: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and is characterized by aggressive tumor behavior coupled with poor prognosis. Various etiologies have been linked to HCC development, most prominently chronic hepatitis B and C virus infections as well as chronic alcohol consumption. In approximately 10% of HCCs, the etiology remains cryptic; however, recent epidemiological data suggest that most of these cryptogenic HCCs develop due to nonalcoholic steatohepatitis. To identify etiology-dependent DNA copy number aberrations and genes relevant to hepatocarcinogenesis, we performed array-based comparative genomic hybridization of 63 HCCs of well-defined etiology and 4 HCC cell lines followed by gene expression profiling and functional analyses of candidate genes. For a 10-megabase chromosome region on 8q24, we observed etiology-dependent copy number gains and MYC overexpression in viral and alcohol-related HCCs, resulting in up-regulation of MYC target genes. Cryptogenic HCCs showed neither 8q24 gains, nor MYC overexpression, nor target gene activation, suggesting that tumors of this etiology develop by way of a distinct MYC-independent pathomechanism. Furthermore, we detected several etiology-independent small chromosome aberrations, including amplification of MDM4 on 1q32.1 and frequent gains of EEF1A2 on 20q13.33. Both genes were overexpressed in approximately half the HCCs examined, and gene silencing reduced cell viability as well as proliferation and increased apoptosis rates in HCC cell lines.
  
  
  CONCLUSIONS
  Our findings suggest that MDM4 and EEF1A2 act as etiology-independent oncogenes in a significant percentage of HCCs.
authors.affiliation: Division of Molecular Genetics, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Schlaeger
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Claudia
authors.initials: C
authors.lastname: Schiller
authors.forename: Peter
authors.initials: P
authors.lastname: Bewerunge
authors.forename: Arianeb
authors.initials: A
authors.lastname: Mehrabi
authors.forename: Grischa
authors.initials: G
authors.lastname: Toedt
authors.forename: Jörg
authors.initials: J
authors.lastname: Kleeff
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D005784:Gene Amplification; D017353:Gene Deletion; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion