ABSTRACT
Objective@#To investigate the molecular markers of copy number aberrations (CNAs) of genes related to extrohepatic metastasis-free survival after the operation for hepatocellular carcinoma (HCC).@*Methods@#The CNA status of 20 candidate genes in 66 HCC samples was detected by microarray comparative genomic hybridization. The associations between gene CNAs and extrohepatic metastasis-free survival were evaluated using the Cox regression model, Log-rank test, and Kaplan-Meier survival analysis.@*Results@#Multivariate Cox analysis revealed that the independent risk factors for metastasis-free survival were MDM4 gain (hazard ratio [HR] = 2.74, 95% confidence interval [CI] = 1.18-6.37, P < 0.05), APC loss (HR = 8.43, 95% CI = 2.48-28.66, P < 0.01), and BCL2L1 gain (HR = 3.45, 95% CI = 1.13-10.52, P < 0.05) and the independent protective factor was FBXW7 loss (HR = 0.32, 95% CI = 0.12-0.89, P < 0.05). By stepwise Cox regression analysis, three CNAs related to metastasis-free survival were screened out: MDM4 gain (HR = 2.71, 95% CI = 1.11-6.64, P < 0.05), APC loss (HR = 7.19, 95% CI = 1.88-27.60, P < 0.005), and FBXW7 loss (HR = 0.16, 95% CI = 0.05-0.46, P < 0.01). There were significant differences in metastasis-free survival rate between the HCC patients with FBXW7 loss and without MDM4 gain or APC loss, those with MDM4 gain and/or APC loss and without FBXW7 loss, and those with other CNA combinations (log-rank test, P < 0.01).@*Conclusion@#MDM4 gain, APC loss, and FBXW7 loss are the independent prognostic factors for extrohepatic metastasis-free survival after the operation for HCC and can be used to predict the risk of extrohepatic metastasis after the operation for HCC.
ABSTRACT
Objective To investigate the relationship between chromosome 6p copy number alterations (CNAs) and postoperative intrahepatic recurrence of hepatocellular carcinoma (HCC);and to screen for the target genes in CNA(s).Methods Array comparative genomic hybridization (CGH) and expression arrays were used to detect CNAs and differences in gene expression, respectively.The associations between CNAs in 6p and HCC recurrence were analyzed using the log-rank test, the Kaplan-Meier curves and the Cox proportional hazards models on 66 patients who had been follow-up for 2.6 ～ 73.3 months.The differentially expression of genes in the potentially recurrence-related CNAs were further evaluated by the MannWhitney U test on 117 HCCs, which included 109 cases with paired array CGH and expression data.Results 6p CNAs were detected in 46 (69.7％) of the 66 HCCs.Of the 8 CNAs with the most frequent recurrence of over 20％ , a gain at 6p21.1 was independently associated with a 2.3-fold (95％ CI =1.1 ～ 5.1, P ＜ 0.05) increased risk for intrahepatic recurrence and with a more pronounced 3.3-fold (95％ CI =1.4 ～ 8.2, P ＜0.05) risk for early recurrence (≤ 1 year).A panel of 9 genes, including BYSL and RPL7L1 within the documented 6p21.1, were observed to be upregulated in HCCs with 6p21.1 gain when compared with HCCs without (all P ＜ 0.05).A high BYSL expression significantly correlated with a larger tumor size (＞ 6 cm), vascular invasion and advanced tumor stage (all P ＜ 0.05), and high RPL7L1 expression significantly correlated with vascular invasion and advanced tumor stage (all P ＜ 0.05).Conclusion A gain at 6p21.1 was an independently prognostic marker for intrahepatic recurrence of postoperative HCC, particular for early recurrence, and BYSL and RPL7L1 might be the target genes in the recurrence-related 6p21.1 gain.