title: Genomic copy number alterations with transcriptional deregulation at 6p identify an aggressive HCC phenotype.
abstract: Genomic analyses have revealed the enormous heterogeneity in essentially all cancer types. However, the identification of precise subtypes, which are biologically informative and clinically useful, remains a challenge. The application of integrative analysis of multilayered genomic profiles to define the chromosomal regions of genomic copy number alterations with concomitant transcriptional deregulation is posited to provide a promising strategy to identify driver targets. In this study, we performed an integrative analysis of the DNA copy numbers and gene expression profiles of hepatocellular carcinoma (HCC). By comparing DNA copy numbers between HCC subtypes based on gene expression pattern, we revealed the DNA copy number alteration with concordant gene expression changes at 6p21-p24 particularly in the HCC subtype of aggressive phenotype without expressing stemness genes. Among the genes at 6p21-p24, we identified IER3 as a potential driver. The clinical utility of IER3 copy numbers was demonstrated by validating its clinical correlation with independent cohorts. In addition, short hairpin RNA-mediated knock-down experiment revealed the functional relevance of IER3 in liver cancer progression. In conclusion, our results suggest that genomic copy number alterations with transcriptional deregulation at 6p21-p24 identify an aggressive HCC phenotype and a novel functional biomarker.
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Suwon 443-721, Korea.
authors.forename: So Mee
authors.initials: SM
authors.lastname: Kwon
authors.forename: Dong-Sik
authors.initials: DS
authors.lastname: Kim
authors.forename: Nam Hee
authors.initials: NH
authors.lastname: Won
authors.forename: Soo Jeong
authors.initials: SJ
authors.lastname: Park
authors.forename: Yong-Joon
authors.initials: YJ
authors.lastname: Chwae
authors.forename: Ho Chul
authors.initials: HC
authors.lastname: Kang
authors.forename: Soo Hwan
authors.initials: SH
authors.lastname: Lee
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Baik
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Hyun Goo
authors.initials: HG
authors.lastname: Woo
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; C099815:IER3 protein, human; D008565:Membrane Proteins; D034741:RNA, Small Interfering