Background: CpG island methylator phenotype (CIMP), characterized by simultaneous methylation of multiple tumor suppressor genes (TSGs), has been reported to be associated with biological malignancy in many cancers. Whether CIMP is potentially predictive of clinical outcome in hepatocellular carcinoma (HCC) remains unknown.
Methods: We investigated the methylation status of ten TSGs and CIMP in 115 samples of HCC and 48 samples of corresponding nonneoplastic liver tissues using a methylation-specific polymerase chain reaction.
Results: The methylation frequencies of the ten genes examined in HCC were 40.0% for p14 ( ARF ), 60.9% for p15 ( INK4b ), 70.4% for p16 ( INK4a ), 34.8% for p73, 70.4% for GSTP1, 64.3% for MGMT, 13.0% for hMLH1, 59.1% for RARbeta, 82.6% for SOCS-1, and 80.9% for OPCML. CIMP+ (with six or more methylated genes) was detected in 68 (59.1%) of 115 HCCs and none of 48 nonneoplastic liver tissues. On stratified univariate analysis, patients with tumor-node-metastasis (TNM) stage I HCC with CIMP+ had significantly shorter overall survival (OS) (P = 0.002) and recurrence-free survival (RFS) (P = 0.042) than those with CIMP-. Furthermore, multivariate analysis revealed CIMP+ as an independent prognostic factor for both OS [hazard ratio (HR), 12.266; P = 0.015] and RFS (HR, 2.275; P = 0.032) in TNM stage I patients.
Conclusions: CIMP+ may specifically define a subgroup of patients with unfavorable outcome in TNM stage I HCC. Examination of CIMP status may be useful for stratifying prognosis of patients with early-stage HCC and identifying patients who are at higher risk for recurrence.