title: Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma.
abstract: BACKGROUND
  Despite the recent identification of several prognostic gene signatures, the lack of common genes among experimental cohorts has posed a considerable challenge in uncovering the molecular basis underlying hepatocellular carcinoma (HCC) recurrence for application in clinical purposes. To overcome the limitations of individual gene-based analysis, we applied a pathway-based approach for analysis of HCC recurrence.
  
  
  RESULTS
  By implementing a permutation-based semi-supervised principal component analysis algorithm using the optimal principal component, we selected sixty-four pathways associated with hepatitis B virus (HBV)-positive HCC recurrence (p < 0.01), from our microarray dataset composed of 142 HBV-positive HCCs. In relation to the public HBV- and public hepatitis C virus (HCV)-positive HCC datasets, we detected 46 (71.9%) and 18 (28.1%) common recurrence-associated pathways, respectively. However, overlap of recurrence-associated genes between datasets was rare, further supporting the utility of the pathway-based approach for recurrence analysis between different HCC datasets. Non-supervised clustering of the 64 recurrence-associated pathways facilitated the classification of HCC patients into high- and low-risk subgroups, based on risk of recurrence (p < 0.0001). The pathways identified were additionally successfully applied to discriminate subgroups depending on recurrence risk within the public HCC datasets. Through multivariate analysis, these recurrence-associated pathways were identified as an independent prognostic factor (p < 0.0001) along with tumor number, tumor size and Edmondson's grade. Moreover, the pathway-based approach had a clinical advantage in terms of discriminating the high-risk subgroup (N = 12) among patients (N = 26) with small HCC (<3 cm).
  
  
  CONCLUSIONS
  Using pathway-based analysis, we successfully identified the pathways involved in recurrence of HBV-positive HCC that may be effectively used as prognostic markers.
authors.affiliation: Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea. buykim@kiom.re.krc.
authors.forename: Bu-Yeo
authors.initials: BY
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. dwchoi@skku.edu.|Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. dwchoi@skku.edu.
authors.forename: Dong Wook
authors.initials: DW
authors.lastname: Choi
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. 26012601@hanmail.net.
authors.forename: Seon Rang
authors.initials: SR
authors.lastname: Woo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. prettyer00@hanmail.net.|Department of Pathology and BK 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. prettyer00@hanmail.net.
authors.forename: Eun-Ran
authors.initials: ER
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. jg-2@nate.com.
authors.forename: Je-Geun
authors.initials: JG
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. kies6loes@naver.com.
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, USA. imhoi.koo@louisville.edu.
authors.forename: Imhoi
authors.initials: I
authors.lastname: Koo
authors.affiliation: Department of Pathology, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. sunhoo@kcch.re.kr.
authors.forename: Sun-Hoo
authors.initials: SH
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. chulju@kirams.re.kr.|Department of Internal Medicine, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. chulju@kirams.re.kr.
authors.forename: Chul Ju
authors.initials: CJ
authors.lastname: Han
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. lull2@kcch.re.kr.|Department of Surgery, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. lull2@kcch.re.kr.
authors.forename: Sang Bum
authors.initials: SB
authors.lastname: Kim
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. yeomyi@kribb.re.kr.
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea. sukjini@kribb.re.kr.
authors.forename: Suk-Jin
authors.initials: SJ
authors.lastname: Yang
authors.affiliation: Department of Statistics, Korea University, Seoul, Korea. lilyu@hanmail.net.|Korean Medicine Clinical Trial Center, Kyung Hee University Oriental Medicine Hospital, Seoul, Korea. lilyu@hanmail.net.
authors.forename: Ami
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Statistics, Korea University, Seoul, Korea. jael@korea.ac.kr.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea. tripj@snu.ac.kr.
authors.forename: Ja June
authors.initials: JJ
authors.lastname: Jang
authors.affiliation: Laboratory of Toxicology and Research Institute for Veterinary Science and College of Veterinary Medicine, Seoul National University, Seoul, Korea. mchotox@snu.ac.kr.
authors.forename: Myung-Haing
authors.initials: MH
authors.lastname: Cho
authors.affiliation: Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea. wkjeon@kiom.re.kr.
authors.forename: Won Kyung
authors.initials: WK
authors.lastname: Jeon
authors.affiliation: Department of Pathology and BK 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea. young0608@yuhs.ac.
authors.forename: Young Nyun
authors.initials: YN
authors.lastname: Park
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. kssuh@snu.ac.kr.
authors.forename: Kyung-Suk
authors.initials: KS
authors.lastname: Suh
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-dong, Nowon-ku, Seoul, 139-706, Korea. khlee@kcch.re.kr.|Herbal Medicine Research Division, Korea Institute of Oriental Medicine, Daejeon, Korea. khlee@kcch.re.kr.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
mesh_terms: D000328:Adult; D000465:Algorithms; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology; D016000:Cluster Analysis; D016208:Databases, Factual; D018572:Disease-Free Survival; D005260:Female; D016174:Hepacivirus / Q000302:isolation & purification; D006509:Hepatitis B / Q000150:complications / Q000175:diagnosis* / Q000821:virology; D006515:Hepatitis B virus / Q000302:isolation & purification; D006801:Humans; D008113:Liver Neoplasms / Q000150:complications / Q000175:diagnosis* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D025341:Principal Component Analysis; D011379:Prognosis; D012306:Risk