title: Genome-wide DNA methylation profiles in liver tissue at the precancerous stage and in hepatocellular carcinoma.
abstract: To clarify genome-wide DNA methylation profiles during hepatocarcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification was performed on 126 tissue samples. The average numbers of BAC clones showing DNA hypo- or hypermethylation increased from noncancerous liver tissue obtained from patients with hepatocellular carcinomas (HCCs) (N) to HCCs. N appeared to be at the precancerous stage, showing DNA methylation alterations that were correlated with the future development of HCC. Using Wilcoxon test, 25 BAC clones, whose DNA methylation status was inherited by HCCs from N and were able to discriminate 15 N samples from 10 samples of normal liver tissue obtained from patients without HCCs (C) with 100% sensitivity and specificity, were identified. The criteria using the 25 BAC clones were able to discriminate 24 additional N samples from 26 C samples in the validation set with 95.8% sensitivity and 96.2% specificity. Using Wilcoxon test, 41 BAC clones, whose DNA methylation status was able to discriminate patients who survived more than 4 years after hepatectomy from patients who suffered recurrence within 6 months and died within a year after hepatectomy, were identified. The DNA methylation status of the 41 BAC clones was correlated with the cancer-free and overall survival rates of patients with HCC. Multivariate analysis revealed that satisfying the criteria using the 41 BAC clones was an independent predictor of overall outcome. Genome-wide alterations of DNA methylation may participate in hepatocarcinogenesis from the precancerous stage, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication.
authors: Pathology Division, National Cancer Center Research Institute, Tokyo, Japan.
authors: Eri
authors: E
authors: Arai
authors: Saori
authors: S
authors: Ushijima
authors: Masahiro
authors: M
authors: Gotoh
authors: Hidenori
authors: H
authors: Ojima
authors: Tomoo
authors: T
authors: Kosuge
authors: Fumie
authors: F
authors: Hosoda
authors: Tatsuhiro
authors: T
authors: Shibata
authors: Tadashi
authors: T
authors: Kondo
authors: Sana
authors: S
authors: Yokoi
authors: Issei
authors: I
authors: Imoto
authors: Johji
authors: J
authors: Inazawa
authors: Setsuo
authors: S
authors: Hirohashi
authors: Yae
authors: Y
authors: Kanai
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D022202:Chromosomes, Artificial, Bacterial; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011230:Precancerous Conditions / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis
chemical_list: D004273:DNA, Neoplasm