Comprehensive allelotype study of hepatocellular carcinoma: Potential differences in pathways to hepatocellular carcinoma between hepatitis B virus-positive and -negative tumors

To examine the role of the loss of heterozygosity (LOH) in hepatitis-related carcinogenesis, we performed a genome-wide scan of LOH in 44 tumors of hepatocellular carcinoma (HCC) using 216 microsatellite markers throughout all human chromosomes. A high frequency of LOH (>30% of informative cases) was observed at 33 loci on chromosome arms 4q; 6q, 8p, 8q, 9p,9q, 13q, 16p, 16q, 17p, and 19p. LOH on 19p has not yet been reported, and that appears to be a new candidate in the search for tumor suppressor genes. High rates of LOH are correlated with hepatitis B virus (HBV) positivity, poorly differentiated tumors, vascular invasion, and intrahepatic metastasis (P < .0001). LOH on 13q and 16q occurred more frequently in HBV(+) patients (P < .0001), and LOH on 6q occurred more frequently in virus-negative patients (P < .001). The frequency of LOH on 4q and 13q was significantly lower in well-differentiated tumors than in moderately and poorly differentiated tumors (P < .01). In contrast, LOB on 6q was frequently detected in well-differentiated tumors compared with other histological subclasses (P < .001). Our results suggest that LOH on 6q may play an important role in the early stage of hepatocarcinogenesis in virus-negative patients, but different mechanisms might underlie the initial step to carcinogenesis in HBV(+) patients. LOH on 13q and 16q may play an essential role in the progression of HBV( +) tumors. Further studies of fine deletion mapping on chromosomes 13q and 16q are required to define the genomic segments on which putative tumor suppressor genes responsible for HBV(+) tumors exist.