Allelic imbalances and homozygous deletion on 8p23.2 for stepwise progression of hepatocarcinogenesis.
Early hepatocellular carcinoma (eHCC) originates from the hepatocytes of chronic liver disease and develops into classical hepatocellular carcinoma (HCC). To identify sequential genetic changes in multistep hepatocarcinogenesis, we analyzed molecular karyotypes using oligonucleotide genotyping 50K arrays. First, 1q21.3-44 gain and loss of heterozygosity (LOH) on 1p36.21-36.32 and 17p13.1-13.3 were frequently observed in eHCC, but not in chronic liver diseases, suggesting that such chromosomal aberrations are early, possibly causative events in liver cancer. Next, we detected 25 chromosomal loci associated with liver cancer progression in five HCCs with nodule-in-nodule appearance, in which the inner nodule develops within eHCC lesion. Using these chromosomal regions as independent variables, decision tree analysis was applied on 14 early and 25 overt HCCs, and extracted combination of chromosomal gains on 5q11.1-35.3 and 8q11.1-24.3 and LOH on 4q11-34.3 and 8p11.21-23.3 as distinctive attributes, which can classify early and overt HCCs recursively. In these four altered regions identified as late events of hepatocarcinogenesis, two tumors in 32 overt HCCs analyzed in the present study and one in a set of independent samples of 36 overt HCCs in our previous study harbored a homozygous deletion near the CSMD1 locus on 8p23.2. CSMD1 messenger RNA expression was decreased in HCC without 8p23.2 deletion, possibly due to hypermethylation of the CpG islands in its promoter region.


CONCLUSIONS
1q gain and 1p and 17p LOH are early molecular events, whereas gains in 5q and 8q and LOH on 4q and 8p only occur in advanced HCC, and inactivation of the putative suppressor gene, CSMD1, may be the key event in progression of liver cancer.
Midorikawa
Yutaka
Y
Division of Genome Science, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.
Yamamoto
Shogo
S
Tsuji
Shingo
S
Kamimura
Naoko
N
Ishikawa
Shumpei
S
Igarashi
Hisaki
H
Makuuchi
Masatoshi
M
Kokudo
Norihiro
N
Sugimura
Haruhiko
H
Aburatani
Hiroyuki
H
D022981:Allelic Imbalance / Q000235:genetics*; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000601:surgery; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002898:Chromosomes, Human, Pair 8; D004273:DNA, Neoplasm / Q000235:genetics; D018450:Disease Progression; D014644:Genetic Variation; D006498:Hepatectomy; D022781:Hepatocytes / Q000473:pathology; D006720:Homozygote; D006801:Humans; D008107:Liver Diseases / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000601:surgery; D019656:Loss of Heterozygosity; D020411:Oligonucleotide Array Sequence Analysis; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017384:Sequence Deletion
D004273:DNA, Neoplasm; D012334:RNA, Neoplasm