title: Oxidative stress pathways in noncancerous human liver tissue to predict hepatocellular carcinoma recurrence: a prospective, multicenter study.
abstract: The prediction of cancer recurrence holds the key to improvement of the postoperative prognosis of patients. In this study, the recurrence of early-stage hepatocellular carcinoma (HCC) after curative hepatectomy was analyzed by the genome-wide gene-expression profiling on cancer tissue and the noncancerous liver tissue. Using the training set of 78 cases, the cytochrome P450 1A2 (CYP1A2) gene in noncancerous liver tissue was identified as the predictive candidate for postoperative recurrence (hazard ratio [HR], 0.447; 95% confidence interval [CI], 0.249-0.808; P = 0.010). Multivariate analysis revealed the statistically significant advantage of CYP1A2 down-regulation to predict recurrence (odds ratio, 0.534; 95% CI, 0.276-0.916; P = 0.036), and the expression of CYP1A2 protein was confirmed immunohistochemically. An independently multi-institutional cohort of 211 patients, using tissue microarrays, validated that loss of expression of CYP1A2 in noncancerous liver tissue as the only predictive factor of recurrence after curative hepatectomy for early-stage HCC (HR, 0.480; 95% CI, 0.256-0.902; P = 0.038). Gene set-enrichment analysis revealed close association of CYP1A2 down-regulation with oxidative stress pathways in liver tissue (P < 0.001, false discovery rate [FDR] = 0.042; P = 0.006, FDR = 0.035). Our results indicate these pathways as the molecular targets to prevent recurrence, as well as the potential prediction of the super high-risk population of HCC using liver tissue.
authors: Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Shinji
authors: S
authors: Tanaka
authors: Kaoru
authors: K
authors: Mogushi
authors: Mahmut
authors: M
authors: Yasen
authors: Daisuke
authors: D
authors: Ban
authors: Norio
authors: N
authors: Noguchi
authors: Takumi
authors: T
authors: Irie
authors: Atsushi
authors: A
authors: Kudo
authors: Noriaki
authors: N
authors: Nakamura
authors: Hiroshi
authors: H
authors: Tanaka
authors: Masakazu
authors: M
authors: Yamamoto
authors: Norihiro
authors: N
authors: Kokudo
authors: Tadatoshi
authors: T
authors: Takayama
authors: Seiji
authors: S
authors: Kawasaki
authors: Michiie
authors: M
authors: Sakamoto
authors: Shigeki
authors: S
authors: Arii
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D016001:Confidence Intervals; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D056726:Genetic Association Studies; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D046228:Microarray Analysis; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D016017:Odds Ratio; D018384:Oxidative Stress / Q000235:genetics*; D011237:Predictive Value of Tests; D011446:Prospective Studies; D012016:Reference Values; D015203:Reproducibility of Results; D016610:Tissue Embedding
chemical_list: D019388:Cytochrome P-450 CYP1A2