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Recurrence-associated pathways in hepatitis B virus-positive hepatocellular carcinoma

 Eun-Ran Park ; Je-Geun Lee ; Seon Rang Woo ; Dong Wook Choi ; Bu-Yeo Kim ; Su-Hyeon Kim ; Imhoi Koo ; Sun-Hoo Park ; Chul Ju Han ; Sang Bum Kim ; Young Il Yeom ; Suk-Jin Yang ; Ami Yu ; Jae Won Lee ; Ja June Jang ; Myung-Haing Cho ; Won Kyung Jeon ; Young Nyun Park ; Kyung-Suk Suh ; Kee-Ho Lee 
 BMC Genomics, Vol.16 : 279, 2015 
Journal Title
 BMC Genomics 
Issue Date
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.
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