High-throughput tissue microarray analysis of c- myc activation in chronic liver diseases and hepatocellular carcinoma

Abstract

Amplification of 8q23-qter is common in human hepatocellular carcinoma (HCC). c- myc, an oncogene located on 8q24, may be important in hepatocarcinogenesis. The present study aimed to evaluate c- myc activation in hepatocarcinogenesis and its clinicopathological significance. High-throughput analysis of c- myc gene amplification and expression using dual-color fluorescence in situ hybridization and immunohistochemistry was performed on tissue microarrays consisting of 458 liver samples comprising HCCs, nontumorous livers and normal livers. HCCs demonstrated frequent c- myc amplification (30% when corrected for chromosome 8 aneusomy). In contrast, the noncancerous livers, which were mostly chronic hepatitis and cirrhosis, exhibited no c- myc amplification. Despite c- myc amplification, the HCCs exhibited less nuclear c- myc expression than the livers with chronic liver diseases and normal livers ( P <0.001 and 0.004, respectively). The HCCs also had less cytoplasmic c- myc staining than the livers with chronic liver diseases ( P = 0.002). Despite their absence of c- myc amplification, however, the livers with chronic disease had significantly increased expression of both nuclear and cytoplasmic c- myc protein compared with normal livers ( P = 0.015 and 0.009, respectively). Clinicopathologically, the reduction in nuclear c- myc was more marked in HCCs with venous permeation and absence of tumor encapsulation ( P = 0.013 and 0.021, respectively), whereas HCCs with cytoplasmic c- myc were positively associated with larger tumor size ( P = 0.027). There was no significant association between c- myc amplification and protein expression levels in HCC. Our results suggest that overexpression of c- myc in chronic liver diseases may play an important role in the predisposition to hepatocarcinogenesis. Although c- myc was amplified in HCC, there appears to be a tight regulation by independent pathways of c- myc activation in hepatocarcinogenesis.