Genomic copy number alterations with transcriptional deregulation at 6p identify an aggressive HCC phenotype

Genomic analyses have revealed the enormous heterogeneity inessentially all cancer types. However, the identification of precisesubtypes, which are biologically informative and clinically useful, remains a challenge. The application of integrative analysis ofmultilayered genomic profiles to define the chromosomal regionsof genomic copy number alterations with concomitant transcriptionalderegulation is posited to provide a promising strategy toidentify driver targets. In this study, we performed an integrativeanalysis of the DNA copy numbers and gene expression profiles ofhepatocellular carcinoma (HCC). By comparing DNA copy numbersbetween HCC subtypes based on gene expression pattern, we revealed the DNA copy number alteration with concordantgene expression changes at 6p21-p24 particularly in the HCCsubtype of aggressive phenotype without expressing stemnessgenes. Among the genes at 6p21-p24, we identified IER3 as apotential driver. The clinical utility of IER3 copy numbers wasdemonstrated by validating its clinical correlation with independentcohorts. In addition, short hairpin RNA-mediated knockdownexperiment revealed the functional relevance of IER3 inliver cancer progression. In conclusion, our results suggest thatgenomic copy number alterations with transcriptional deregulationat 6p21-p24 identify an aggressive HCC phenotype and anovel functional biomarker.