title: Overlapping high-resolution copy number alterations in cancer genomes identified putative cancer genes in hepatocellular carcinoma.
abstract: Recurrent cancer genome aberrations are indicators of residing crucial cancer genes. Although recent advances in genomic technologies have led to a global view of cancer genome aberrations, the identification of target genes and biomarkers from the aberrant loci remains difficult. To facilitate searches of cancer genes in human hepatocellular carcinoma (HCC), we established a comprehensive protocol to analyze copy number alterations (CNAs) in cancer genomes using high-density single nucleotide polymorphism arrays with unpaired reference genomes. We identified common HCC genes by overlapping the shared aberrant loci in multiple cell lines with functional validation and clinical implications. A total of 653 amplicons and 57 homozygous deletions (HDs) were revealed in 23 cell lines. To search for novel HCC genes, we overlapped aberrant loci to uncover 6 HDs and 126 amplicons shared by at least two cell lines. We selected two novel genes, fibronectin type III domain containing 3B (FNDC3B) at the 3q26.3 overlapped amplicon and solute carrier family 29 member 2 (SLC29A2) at the 11q13.2 overlapped amplicon, to investigate their aberrations in HCC tumorigenesis. Aberrant up-regulation of FNDC3B and SLC29A2 occurred in multiple HCC data sets. Knockdown of these genes in amplified cells decreased cell proliferation, anchorage-independent growth, and tumor formation in xenograft models. Importantly, up-regulation of SLC29A2 in HCC tissues was significantly associated with advanced stages (P = 0.0031), vascular invasion (P = 0.0353), and poor patient survival (P = 0.0325). Overexpression of FNDC3B or SLC29A2 in unamplified HCC cells promoted cell proliferation through activation of the signal transducer and activator of transcription 3 signaling pathway.
  
  
  CONCLUSIONS
  A standardized genome-wide CNA analysis protocol using data from user-generated or public domains normalized with unpaired reference genomes has been established to facilitate high-throughput detection of cancer genes as significant target genes and biomarkers for cancer diagnosis and therapy.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chian-Feng
authors.initials: CF
authors.lastname: Chen
authors.forename: En-Chi
authors.initials: EC
authors.lastname: Hsu
authors.forename: Kuen-Tyng
authors.initials: KT
authors.lastname: Lin
authors.forename: Pang-Hsien
authors.initials: PH
authors.lastname: Tu
authors.forename: Hung-Wei
authors.initials: HW
authors.lastname: Chang
authors.forename: Chin-Hui
authors.initials: CH
authors.lastname: Lin
authors.forename: Yann-Jang
authors.initials: YJ
authors.lastname: Chen
authors.forename: De-Leung
authors.initials: DL
authors.lastname: Gu
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Hsu
authors.forename: Yuh-Shan
authors.initials: YS
authors.lastname: Jou
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D003114:Colony-Forming Units Assay; D055785:Gene Knockdown Techniques; D052138:Genes, Neoplasm / Q000235:genetics*; D016678:Genome; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D034622:RNA Interference