ARRAY COMPARATIVE GENOMIC HYBRIDIZATION AND TRANSCRIPTOME ANALYSES OF HEPATOCELLULAR CARCINOMA

Abstract

Characterizing the genomic abnormalities underlying hepatocellular carcinoma (HCC) is crucial for understanding the molecular mechanisms of liver cancer development. Most cytogenetic analyses of HCC were however performed using low resolution conventional CGH. In this study, high resolution array CGH comprising of 42,463 probes was used to elucidate the DNA copy number changes for 15 pairs of HCC tumors and non-tumorous tissues and 12 HCC cell lines. These tumors were also subjected to transcriptome profiling to identify corresponding transcriptional de-regulation. It was found that DNA copy number gains involving 1q and 8q, and losses involving 4q, 8p, 13q, 16q and 17p were the most frequent in HCC. Importantly, array CGH of the HCC cell lines demonstrated that the common chromosomal imbalances on 8q, 16q and 17p in patient tumors were not reflected in the cell lines, and additional aberrations on 9p, 18q and 20q were accumulated possibly during in vitro culture. Gain on 1q and losses on 4q, 8p and 13q however, remained prevalent in cell lines. Computation of pairwise Pearson¿s correlation between log2 fold change values of corresponding array CGH probes in the cell lines and a pooled tumor sample that was derived from the average of the 15 tumors revealed that Hep3B was most representative of copy number changes in patient tumors. It reported an average correlation of 0.6 across all somatic chromosomes. HepG2 was the least representative cell line with an average correlation of 0.11. Integrative analysis of copy number and transcriptome changes in the 15 tumors identified a set of 44 genes whose expression positively correlated with copy number changes, of which many resided on 8p. The consistent involvement of 8p in HCC and cell lines supported an important role for it in tumor formation and growth.