Clinical implication of recurrent copy number alterations in hepatocellular carcinoma and putative oncogenes in recurrent gains on 1q

Hepatocellular carcinoma (HCC) is one of the most common human malignancies and responsible for ~5% of all cancer-related deaths in the world.1 Given that the overall HCC incidence is still rising and prognosis of the disease remains poor, it is important to develop effective diagnostic and therapeutic modalities based on sound biological insights into hepatocarcinogenesis.2,3 The copy number alterations observed in human solid tumors are known to contribute to the tumorigenesis by affecting the activities of cancer-related genes in the altered chromosomal regions.4 Thus, genome-wide mapping of copy number alterations in cancer can facilitate the identification of cancer-related genes, which will improve the understanding of tumorigenesis. Using conventional cytogenetic tools such as comparative genomic hybridization (CGH), copy number gains on 1q, 8q and 20q, along with losses on 1p, 4q, 8p, 13q, 16q and 17p have been previously identified in HCC.5-7 However, the resolution of conventional cytogenetic analysis is insufficient to precisely identify submicroscopic changes. Recently introduced array-CGH, the combination of conventional CGH and microarray technology, enabled high-resolution screening of genome-wide copy number alterations containing potential cancer-related genes.8,9 Through array-CGH analysis, novel oncogenes such as JAB1 or differentiation-specific regions have been identified in HCC.5,10 Also etiology-dependent copy number alterations and genes relevant to hepatocarcinogenesis were suggested in HCC.11 But, it is still difficult to identify the biologically relevant changes and their functional significance in a systematic manner due to the extensive and complex nature of chromosomal alterations. We hypothesized that recurrent copy number changes common to many HCC cases may contain essential genes for hepatocarcinogenesis. Using this strategy, recurrently altered regions (RARs) were defined in 76 primary HCCs using whole-genome array CGH analysis, and the associations between RARs and clinicopathologic features were examined. Also, we functionally categorized the genes located in the RARs.