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Extensive Methylation Is Associated with ß-Catenin Mutations in Hepatocellular Carcinoma: Evidence for Two Distinct Pathways of Human Hepatocarcinogenesis

¹ Department of Internal Medicine, Division of Gastroenterology, Sammons Cancer Center and the Baylor Research Institute, Baylor University Medical Center, Dallas, Texas and Departments of ² Gastroenterology and Hepatology and ³ Gastroenterological Surgery, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan

Requests for reprints: C. Richard Boland, Gastrointestinal Cancer Research Laboratory (250 Hoblitzelle), Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX 75246. Phone: 214-820-2692; Fax: 214-818-9292; E-mail: RickBo{at}BaylorHealth.Edu.

Hepatocellular carcinoma (HCC) with p53 mutations is usually characterized by extensive chromosomal instability (CIN), whereas those with ß-catenin mutations have relatively less CIN and the molecular pathogenesis of these tumors is unknown. Methylation of CpG dinucleotides in the promoters of cancer-related genes is another characteristic feature of HCCs. The aim of this study was to determine the contribution of the methylator phenotype to HCC and its relationship to genomic instability. Fractional allelic loss (FAL) was determined using 400 microsatellite markers in 81 HCCs and 77 corresponding noncancerous livers as a measure of CIN. Methylation of 21 genetic loci was quantitated using combined bisulfite restriction analysis. Using hierarchical clustering analysis based upon the quantification of methylation levels, all HCCs were segregated into two groups characterized by either limited or extensive methylation. Mutations in the ß-catenin and p53 genes were determined by DNA sequencing. We found that the methylation levels were significantly higher in the HCCs than in noncancerous livers in 18 of the 21 loci (P values ranged from 0.035 to <0.0001). Among 18 loci, elevated levels of methylation at nine loci were significantly associated with ß-catenin mutations (P values ranged from 0.02 to <0.0001). In addition, the presence of ß-catenin mutations was associated with HCCs in the extensive methylation group (P < 0.0001), whereas p53 mutations correlated with high FAL scores (P = 0.0036). These data suggest that HCCs can be classified into two distinct categories based upon promoter methylation, CIN, and mutations of cancer-related genes. HCCs with extensive methylation harbor frequent ß-catenin mutations, whereas HCCs with high levels of CIN are associated with p53 mutations, suggesting the presence of two independent pathways for the pathogenesis of HCC. [Cancer Res 2007;67(10):4586–94]

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				Correction: Genetic and Epigenetic Pathways in HCC Cancer Res., June 15, 2007; 67(12): 5998 - 5998. [Full Text] [PDF]