The incidence of hepatocellular carcinoma was lower in patients with sustained response to interferon therapy than historical controls and nonresponders. Interferon therapy may decrease the risk for hepatocellular carcinoma in patients with chronic hepatitis C.

The incidence of HCC in Osaka started to decrease by 2000, mainly because of decreased HCV-related HCC.

BACKGROUNDChromosomal instability (CI) leading to aneuploidy is one form of genetic instability, a characteristic feature of various types of cancers. Recent work has suggested that CI can be induced by a spindle assembly checkpoint defect. The aim of the current study was to determine the frequency of a defect of the checkpoint in hepatocellular carcinoma (HCC) and to establish whether alterations of genes encoding the checkpoint were associated with CI in HCC.METHODSAneuploidy and the function of the spindle assembly checkpoint were examined using DNA flow cytometry and morphologic analysis with microtubule disrupting drugs. To explore the molecular basis, the authors examined the expression and alterations of the mitotic checkpoint gene, BUB1, using Northern hybridization and direct sequencing in 8 HCC cell lines and 50 HCC specimens. Furthermore, the authors examined the alterations of other mitotic checkpoint genes, BUBR1, BUB3, MAD2B, and CDC20, using direct sequencing in HCC cell lines with aneuploidy.RESULTSAn impaired spindle assembly checkpoint was found in five (62.5%) of the eight aneuploid cell lines. Transcriptional expressions of the BUB1 gene appeared in all cell lines. While some polymorphic base changes were noted in BUB1, BUBR1, and CDC20, no mutations responsible for impairment of the mitotic checkpoint were found in either the HCC cell lines or HCC specimens, which suggests that these genes did not seem to be involved in tumor development in HCC.CONCLUSIONSThe loss of spindle assembly checkpoint occurred with a high frequency in HCC with CI. However, other mechanisms might also contribute to CI in HCC. Cancer 2002;94:2047–54. © 2002 American Cancer Society.DOI 10.1002/cncr.10448

We investigated the expression of transforming growth factor β1 (TGF‐β1) mRNA in tumor tissues surgically removed from ten patients with hepatocellular carcinoma (HCC). All HCC tissues expressed TGF‐β1 mRNA at different levels, indicating the presence of activated transcription of TGF‐β1 gene in human HCC tissues in vivo. The level of TGF‐β1 mRNA expression showed no relationship to main tumor size or plasma α‐fetoprotein level. Some HCC tissues presenting a relatively low grade of histological differentiation showed the highest levels of TGF‐β1 mRNA expression.

Enhancement of hepatic tumors on sonograms by injection of carbon dioxide microbubbles into the hepatic artery as a contrast material (enhanced ultrasonography) was performed in 43 patients with various histologically confirmed hepatic tumors. Enhanced sonograms were classified into five patterns according to the relative changes of the echo levels between the tumor and the nontumorous parenchyma of the liver as a result of enhancement: hyperechoic change, isoechoic change, hypoechoic change with hyperechoic rim (rim sign), marginal spotty hyperechoic change, and internal spotty hyperechoic change. Eighty-eight percent of hepatocellular carcinomas showed hyperechoic change, 70% of metastatic tumors exhibited hypoechoic change with the rim sign. The marginal spotty hyperechoic change and the internal spotty hyperechoic change were specific for cavernous hemangioma and fibrous granuloma, respectively. This method of enhancement is useful in assessing the nature of liver tumors and in the detection of small nodules in the liver.

ObjectiveAutoimmune hepatitis (AIH) is a chronic progressive liver disease. AIH is composed predominantly of type 1 in Japanese populations. The genetic and environmental factors are associated with the pathogenesis of AIH. HLA-DRB1*03:01 and *04:01 are associated with type 1 AIH in European and *04:05 in Japanese populations. Here, we conducted an HLA association study in order to find HLA alleles or haplotypes predisposing or protective for Japanese AIH.MethodsHLA-DRB1 and DQB1 genotyping of 360 type 1 AIH patients and 1026 healthy controls was performed.ResultsThe predisposing association of DRB1*04:01 (P = 0.0006, corrected P [Pc] = 0.0193, odds ratio [OR] 2.97, 95% confidence interval [CI] 1.62–5.43), DRB1*04:05 (P = 1.89×10−21, Pc = 5.86×10−20, OR 3.41, 95% CI 2.65–4.38), and DQB1*04:01 (P = 4.66×10−18, Pc = 6.99×10−17, OR 3.89, 95% CI 2.84–5.33) and the protective association of DRB1*13:02 (P = 0.0003, Pc = 0.0080, OR 0.48, 95% CI 0.32–0.72) with Japanese type 1 AIH were observed. An association of the DR4/DR8 heterozygous genotype with Japanese AIH was identified for the first time (P = 3.12×10−9, OR 3.52, 95% CI 2.34–5.29). Susceptible diplotypes were DRB1*04:05-DQB1*04:01/DRB1*08:02-DQB1*03:02 (P = 0.0004, OR 24.77, 95% CI 1.45–424.31) and DRB1*04:05-DQB1*04:01/DRB1*08:03-DQB1*06:01 (P = 1.18×10−6, OR 10.64, 95% CI 3.19–35.46). Serum levels of Immunoglobulin G and Immunoglobulin M, International Autoimmune Hepatitis Group score, positive rate of anti-smooth muscle antibodies, and the rate of definite AIH were higher in AIH patients with DRB1*04:05 than without.ConclusionsThe important roles of specific combinations of DRB1 and DQB1 alleles or haplotypes in the pathogenesis of type 1 AIH were suggested. The association of DR4/DR8 heterozygous genotype suggested the pathologic importance of trans-complementing DQα-β heterodimer molecules encoded by DQA1 allele of one haplotype and the DQB1 allele of the other haplotype, as it was proposed in the HLA association studies of Type 1 diabetes.

Primary biliary cholangitis (PBC) is a chronic and cholestatic autoimmune liver disease caused by the destruction of intrahepatic small bile ducts. Our previous genome-wide association study (GWAS) identified six susceptibility loci for PBC. Here, in order to further elucidate the genetic architecture of PBC, a GWAS was performed on an additional independent sample set, then a genome-wide meta-analysis with our previous GWAS was performed based on a whole-genome single nucleotide polymorphism (SNP) imputation analysis of a total of 4,045 Japanese individuals (2,060 cases and 1,985 healthy controls). A susceptibility locus on chromosome 3q13.33 (including ARHGAP31, TMEM39A, POGLUT1, TIMMDC1, and CD80) was previously identified both in the European and Chinese populations and was replicated in the Japanese population (OR = 0.7241, P = 3.5 × 10−9). Subsequent in silico and in vitro functional analyses identified rs2293370, previously reported as the top-hit SNP in this locus in the European population, as the primary functional SNP. Moreover, e-QTL analysis indicated that the effector gene of rs2293370 was Protein O-Glucosyltransferase 1 (POGLUT1) (P = 3.4 × 10−8). This is the first study to demonstrate that POGLUT1 and not CD80 is the effector gene regulated by the primary functional SNP rs2293370, and that increased expression of POGLUT1 might be involved in the pathogenesis of PBC.

Adenomatous hyperplasia (AH) of the liver is considered a precancerous lesion because hepatocellular carcinoma (HCC) has been found in nodules of AH at histologic examination. Contrast material-enhanced ultrasound (US) with intraarterial infusion of carbon dioxide microbubbles was performed in four patients with HCC in AH lesions. In all four patients, a "hyperechoic focus in an area of hypoechoic change" in relation to the adjacent liver was demonstrated, compatible with the minimal vascular change associated with neoplastic transformation and carcinoma development. Because early detection of the minute cancer foci that may develop in an AH nodule is clinically important, this contrast-enhanced US technique may be a useful tool for the detection of these associated lesions.