| Backgrond&Aim: Primary liver cancer (PLC) is the third lethality tumordiseases, which seriously influences human healthy. PLC usually has no symptom inearly stage, and be detected in advanced stages, so curable methods, such as operation,radiofrequency ablation and liver transplantation can be applied. In this way,palliative therapy is very important in PLC treatment. Transarterialchemoembolization (TACE) is the most important approach of palliative therapy.Randomized controlled trail and meta-analysis revealed that TACE can significantlyimprove outcome of advanced PLC patients. However, patients in same tumor stageand had similar clinical characteristics also had different outcomes. Further TACE, asa non-invasion treatment, is hard to acquire tissues of tumor, which made it cannot usemolecular biological or Immunological methods to predict prognosis as operation. Soit is urgently needed new biomarker to predict prognosis of PLC treated by TACE.CD147is an important tumor surface molecule, which is found in many cancers.CD147takes part in tumor progression，metastasis and transformation of tumormetabolism. CD147upregulated in PLC, and unregulation of CD147indicated poorprognosis of PLC patients. Former study showed that CD147and CD98formedCD147-CD98complex to take efforts. CD147-CD98complex interacted withEPCAM and ASCT2, which would influence progression and metabolism of tumorcell. EPCAM is the member of CAM family, which expresses in normal epithelial cell.Furthermore, EPCAM is high expression in many types of tumors. Former studyshowed that EPCAM highly expressed in HCC tissues and upregulation of EPCAMindicated poor prognosis. ASCT2, also called SLC1A5, is a Na+-coupled amino acidtransporter that belongs to SLC1gene family. It accepts only neutral amino acids assubstrates for transport. ASCT2is the important part in transport of Glutamine, sinceGlutamine is significant material in tumor maintaining. Further research found thatASCT2increasingly expressed in several tumors, and following study in cell linesindicated that ASCT2was essential for tumor maintaining and growth. But there wasno report about association between ASCT2and PLC prognosis.Single nuclear polymorphisms (SNP) can reflect difference of geneticbackground among different peoples steadily and concisely. Detecting SNP just need peripheral Blood which is easy to acquire, and with the development of techniqueshigh throughput detection of SNP is achieved. SNP is used in many studies aboutdiseases besides tumors. Former study showed that SNP in EPCAM gene associatedwith risk of breast and cervical cancers. Further study indicated that SNP in EPCAMgene associated with prognosis of non small cell lung cancer. However, there was noreport about association between SNP in EPCAM gene and liver cancer. And formerreport indicated association between SNP in ASCT2gene and the nervous systemdiseases, but no study concerned relationship between SNP in ASCT2gene andcancer.In our study, we intend to assess the association of SNP in EPCAM and ASCT2genewith prognosis of PLC by TACE and find new prognostic biomarker for primary livercancer.Methods: A total of448patients with PLC, whose first-line treatment isTACE, were retrospectively recruited into our study at Eastern Hepatobiliary Surgery Hospital, between February2008and December2011. Then collect clinical data and follow up for prognostic data. Latest follow-up data were obtainedin January2014. For all enrolled patients,5ml of blood sample from each participant was collected and subjected for genomic DNA extraction. SNPs wasselected using a set of Web-based SNP selection tools (freely available at http://snpinfo.niehs.nih.gov/snpinfo/snpfunc.htm) provided by National Institute for Environmental Health Science (NIEHS). Genotyping was carried out using the iPLEX genotyping system (Sequenom, San Diego, CA). The SPSS19.0statisticalpackage (IBM SPSS, statistics19) was used for the statistical analyses. Univariate and multivariate Cox proportional hazard analyses were used to assess thedifferences of overall survival among different subgroups. Kaplan-Meier curvesand log-rank test were used to assess difference of survival rate between different subgroups. Mann-Whitney U test were used to assess difference of tumor size among different genotypes. Three genetic models (additive, dominant and recessive) were applied to assess the association of SNPs with clinical outcomeof HCC patients. All P values were two-sided, and P <0.05was considered asthe threshold of statistical significance.Results: We chose two SNPs (rs1126497and rs1421）in EPCAM gene to furtherstudy. Cox regression analysis of clinical characteristics showed that AFP level of >200ng/mL (HR,1.63;95%CI,1.31-2.03, P <0.0001), tumor size of>5cm (HR,2.53;95%CI,1.96-3.27, P <0.0001), multiple lesions (HR,1.40;95%CI,1.12-1.75, P=0.003), existence of PVTT (HR,2.43;95%CI,1.93-3.05, P <0.0001) and higherdegree of BCLC stage (HR,2.18;95%CI,1.75-2.71, P <0.0001) were prognosticfactor of PLC. No significant association between either of two SNPs in EPCAM geneand PLC overall survival was observed in univariate and multivariate Coxproportional hazard analysis. Stratified analysis showed that patients carryingvariant-containing genotype of rs1126497showed a poor overall survival in134patients with PVTT (HR,1.62;95%CI,1.11-2.39, P=0.013), comparing to thosecarrying the wild-type genotype. Kaplan-Meier curve and log-rank test showed asignificantly shorter median survival time in patients with variant-containing genotypeof rs1126497than those carrying wild-type genotype in patients with PVTT (Log rankP=0.023). Interaction effects between SNPs and clinical characteristics analysisshowed that rs1126497had interaction effects with tumor number (HR,1.34;95%CI,1.01-1.78, P=0.045) and PVTT (HR,1.73;95%CI,1.19-2.51, P=0.004) onprognosis of PLC. Kaplan-Meier curve results verified the results.We chose two SNPs (rs3826793and rs2070246）in ASCT2gene to further study.Multivariate Cox proportional hazard analyses showed that AFP (HR,1.35;95%CI,1.08-1.70, P=0.010), tumor size (HR,1.95;95%CI,1.46-2.61, P <0.0001), PVTTstatus (HR,1.82;95%CI,1.42-2.33, P <0.0001) and BCLC stage (HR,1.54;95%CI,1.20-1.98, P=0.001) were independent prognostic factors of PLC patients treated byTACE. Moreover, combined other therapies could significantly improve prognosis ofPLC (HR,0.43;95%CI,0.31-0.60, P <0.0001)。Cox regression, stratified analysisand Kaplan-Meier curve showed no significant association between SNPs in ASCT2gene and prognosis of PLC. Multivariate logistic regression showed that：patientscarried homozygous variant (VV) genotype of rs2070246had a smaller tumor,compared with wild-type (OR,0.40;95%CI,0.20-0.78, P=0.008). Three geneticmodels analysis showed rs2070246in ASCT2gene showed significant associationwith tumor proliferation (OR,0.32;95%CI,0.17-0.62; P=0.001) in recessive model.Conclusions: rs1126497in EPCAM gene can predict prognosis of PLC patientswith PVTT treated by TACE. rs2070246in ASCT2gene significantly associated withtumor size of PLC. However, the results of our study should be verified by furtherlarge population studies. |
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