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, LOH 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.
Okabe
H
H
Department of Gastroenterological Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. cah19150@pop02.odn.ne.jp
Ikai
I
I
Matsuo
K
K
Satoh
S
S
Momoi
H
H
Kamikawa
T
T
Katsura
N
N
Nishitai
R
R
Takeyama
O
O
Fukumoto
M
M
Yamaoka
Y
Y
D000483:Alleles; D006528:Carcinoma, Hepatocellular / Q000209:etiology / Q000235:genetics* / Q000821:virology; D002882:Chromosomes, Human, Pair 13; D002885:Chromosomes, Human, Pair 16; D005260:Female; D006515:Hepatitis B virus / Q000302:isolation & purification*; D006801:Humans; D008113:Liver Neoplasms / Q000209:etiology / Q000235:genetics* / Q000821:virology; D019656:Loss of Heterozygosity; D008297:Male