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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.
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OBJECTIVE To assess the association of copy number variations (CNVs) in chromosome 17q with the overall survival(OS) of patients with hepatocellular carcinoma(HCC), and to screen for target genes contained in the OS-related CNVs. METHODS A total of 174 HCC cases were enrolled. For 66 patients, the follow-up data was available. High-resolution Agilent Hu-244A array comparative genomic hybridization (aCGH) and Affymetrix U133 Plus 2.0 expression arrays were used to detect CNVs and gene expression of genes from the 17q region, respectively. The association of CNVs and OS was assessed with Log-rank test, Kaplan-Meier survival analysis, and Cox proportional hazards models. The gene expression in HCCs with 17q gain, HCCs without, and non-tumor liver tissues were compared with a Mann-Whitney U test. RESULTS Univariate association analysis showed that copy number gain in 17q25.1-25.3 was significantly associated with reduced OS (Log-rank test, P = 0.00002), and HCC cases with 17q25.1-25.3 gain had a 4.76-fold (95%CI: 2.31-9.81) increased hazard ratio (HR) for death from HCC, as compared to those without the gain. Multivariate Cox proportional hazards regression model revealed 17q25.1-25.3 gain to be an independent prognostic marker for poor OS (HR = 3.17, 95%CI: 1.39-7.26, P = 0.006). The expression levels of 18 genes in 17q25.1-25.3 including SLC9A3R1, GRB2, and TK1 were significantly increased in HCCs with gain than in those without (all P < 0.01) and non-tumor liver tissues (all P < 0.01). CONCLUSION The association of 17q25.1-25.3 gain with reduced OS has indicated that it is a prognostic marker for poor patient survival in HCC, for which SLC9A3R1, GRB2, and TK1 are candidate genes.
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Adult , Aged , Female , Humans , Male , Middle Aged , Carcinoma, Hepatocellular , Genetics , Mortality , Chromosomes, Human, Pair 17 , DNA Copy Number Variations , Liver Neoplasms , Genetics , MortalityABSTRACT
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.
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Objective To investigate the association of chromosome 8p copy number alteration (CNA) with postoperative survival of patients with hepatocellular carcinoma (HCC),and to screen for possible target genes in the survival-related CNA (s) in 8p.Methods 187 HCC patients were enrolled into the study,which included 66 patients whose follow-up data were available and the follow-up was 2.6 ～ 73.3 months.High-resolution Agilent 244K comparative genomic hybridization (CGH) and Affymetrix U133 Plus2.0 expression arrays were used to screen for CNAs and gene expression differences in 8p.The associations between CNAs in 8p and survival were analyzed using the log-rank test,Kaplan-Meier survival analysis and Cox proportional hazards models.The gene expression levels between the groups were compared by the Mann-Whitney U test.Results Copy number loss on 8p12 (31/66,47％) was significantly associated with reduced survival rate,and HCC patients with 8p12 loss had a 4.1-fold (95％ CI =1.8 ～ 9.4,P ＜ 0.05) increased hazard ratio (HR) for death from HCC,as compared to those without the loss.The mRNA expression levels of the 3 genes in 8p12,including TMEM66,DCTN6,and MAK16,were significantly decreased in HCCs with gene loss than in HCCs without the loss (all P ＜ 0.05),and in non-tumorous liver tissues (all P ＜ 0.05).Conclusion Loss of 8p12 is an independent prognostic marker of unfavorable survival for patients with HCC,and underexpression of genes TMEM66,DCTN6,and MAK16,owing to 8p12 loss,contributed to unfavorable prognosis.
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Objective To investigate the possible association between the CCND1 A870G polymorphism and susceptibility to prostate cancer(PCa)in a Chinese population.Methods The CCND1 A870G genotypes were determined by TaqMan assays in 245 PCa cases and age-matched 245 controis.Odds ratios(OR)for PCa and 95%confidence intervals(CI)from unconditional logistic regression models were used to evaluate relative risks.Age,a potential PCa risk factor,was included in the logistic regression models as a covariate in the multivariate analyses on genotype and PCa risk.Results The frequencies for G and A alleles were 0.476,0.524 in PCa cases,and 0.408 and 0.592 in controls,respectively.The G allele was marginally significantly associated with the presence of PCa (P=0.054)and had an increased risk for PCa(OR=1.31,95%CI=1.00-1.72)as compared to theA allele.Compared to AA homozygote,AG heterozygote had a 1.43-fold increased risk(95%CI=0.89-2.31,P=0.142),whereas GG homozygote had a significantly higher 2.02-fold increased risk (95%CI=1.07-3.80,P=0.029)of PCa(Armitage's trend test,P=0.029).The G allele(AG or GG genotype)was more frequently found in PCa patients with metastasis than those without metastasis(P=0.014).Conclusion The G allele of CCND1 A870G is associated with the presence of PCa and GG homozygote is potentially one of the genetic risk factors for PCa in Chinese population.The G allele may be associated with the progression of PCa metastasis.