title: 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.
authors.affiliation: Department of Pathology, Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong.
authors.forename: Kok-Lung
authors.initials: KL
authors.lastname: Chan
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc