| Objective: Ovarian cancer (OC) is one of the most common gynecologicmalignancies and the leading cause of death among cancers of the femalereproductive tract. Due to lack of early symptoms, approximately70%ofovarian cancers present FIGO stage3and4when diagnose, so the overall5-year survival is still about30%. Although the molecular mechanismsunderlying this process are not well characterized, Interferences of apoptosisare associated with the pathogenesis of human diseases including ovariancancer. Fas/FasL pathway plays an important role in the development andprogression of cancer. Studies have shown that the genetic polymorphisms inFas and FasL have been linked to cancer development and progression byaltering their promoter activity and expression. Studies have shown that FASand FASL are aberrant express in ovarian cancer, FAS-1377G/A,-670A/Gand FASL-844T/C single nucleotide polymorphism (SNP) in the promoterregions of Fas and FasL have been linked to their expression alteration, andthus increase the risk to cancer. The aim of this study was to analyzewhether aforementioned SNPs are associated with the risk of EOC. Inaddition, we also evaluated whether the Fas and FasL polymorphisms wereassociated with the survival of EOC.Methods: This case-control study analyses the relationship betweenepithelial ovarian cancer and FAS-1377G/A,-670A/G and FASL-844T/Csingle nucleotide polymorphism. It included342patients with epithelialovarian cancer and344frequency-matched healthy control women. Survivaldata was available for193of the342patients who were inpatients in theFourth Hospital, Hebei Medical University between December2001andAugust2008.Five milliliters of venous blood was drawn from each subject into Vacutainer tubes containing ethylene diamine tetra acetic acid and stored at4°C. Genomic DNA was extracted within1week after sampling byProteinase K (Merck, Darmstadt, Germany) digestion followed by a saltingout procedure according to the method of Miller et al. The genotyping ofSNPs (rs2234767rs1800682rs763110) was analyzed by allelic specificmultiple ligase detection reactions (LDR) method.Statistical analysis was performed using SPSS ver.13.0software package.A probability level of5%was considered significant. The age difference ofcases and frequency-matched controls was analyzed by the t-test.Hardy-Weinberg analysis was performed by comparing the observed andexpected genotype frequencies in study groups using Chi-square test.Comparison of the FAS and FASL genotype distribution in EOC patients andhealthy controls were performed by means of two-sided contingency tablesusing the x2-test. Unconditional logistic regression models were used tocalculate odds ratios (ORs) and their95%confidence intervals (CIs). TheKaplan–Meier procedure was used to estimate the survival time andrecurrence time by genotype and the log-rank test was used to compare thesurvival distributions. Hazard ratios (HR) and95%confidence intervals(95%CI) were estimated using multivariate Cox proportional hazards models,with adjustment for age.Results:1The genotype distribution of Fas-1377G/A, Fas-670A/G and FasL844T/CSNP in the healthy controls did not deviate from the Hardy–Weinbergequilibrium (P=0.97; P=0.36; P=0.55).2Association between the Fas and FasL SNP and the risk of EOC2.1The genotype frequencies of the FAS-1377G/A, G/G,G/A and A/A incontrols and patients were45.6%,43.9%,10.5%and46.5%,43.9%,9.6%,respectively; the G and A allele frequencies were67.6%,32.4%and68.4%,31.6%, respectively. There was no statistically significant difference in thegenotype distributions or allele frequencies of FAS-1377G/A between thepatients and controls (P>0.05; Table1). Stratification analysis showed no statistically different among case patients and control subjects in allele orgenotype distributions of FAS-1377G/A according to the pathological type,clinical stage and patient age of ECO (P>0.05)。2.2The genotype frequencies of the FAS-670G/G,G/A,A/A in controls andpatients were12.8%,49.1%,38.1%å'Œ10.5%,48%,41.5%, respectively; theG and A allele frequencies were37.4%,62.6%å'Œ34.5%,65.5%, respectively.There was no statistically significant difference in the genotype distributionsor allele frequencies of FAS-670A/Gbetween the patients and controls(P>0.05). Stratification analysis showed no statistically different among casepatients and control subjects in allele or genotype distributions of FAS-670A/G according to the pathological type, clinical stage and patient age ofECO (P>0.05)。2.3The genotype frequencies of the FASL-844T/T,T/C,C/C in controls andpatients were7.0%,41.3%,51.7%å'Œ4.4%,34.5%,61.1%(P=0.034),respectively; the T and C allele frequencies were27.6%,72.4%å'Œ21.6%,78.4%, respectively There was statistically significant difference in thegenotype distributions or allele frequencies of FASL-844T/C between thepatients and controls (P=0.010; Table1). Compared to the CC genotype, theTT+TC genotype significantly decreased the risk of epithelial ovarian cancer(OR=0.6895%CI=0.50~0.92). Stratification analysis showed subjectscarrying FASL-844TT+TC genotype significantly decreased the risk of serousovarian cancer (OR=0.52,95%CI=0.34～0.79) according to histologicalsubtypes. When stratified by clinical stage, individuals with the TT+TCgenotype significantly had a relation on the decreased risk of the advancedovarian cancer (OR=0.63,95%CI=0.45～0.89). Furthermore, the lower riskof ovarian cancer was associated with the TT+TC genotype in subjects thatwere50or older, with odds ratio of0.70(95%CI=0.50~0.97).3Association between the Fas and FasL SNP and the survival of EOC3.1The genotype frequencies of the FAS-1377G/G,G/A and A/A in alivesand deaths were54.6%,36.1%,9.2%and35.1%,58.1%,6.8%, respectively.There was statistically significant difference in the genotype distributions or allele frequencies of FAS-1377A/G between the alives and deaths (P=0.02);Compared to the G/G genotype, the GA+AG genotype exhibited a worsesurvival (HR=1.8595%CI=1.15~2.98)。 The genotype frequencies of theFAS-1377G/A, G/G,G/A and A/A in recurrence and non-recurrence were39.5%,52.4%,8.3%å'Œ60.9%,30.4%,8.7%, respectively. There wasstatistically significant difference in the genotype distributions or allelefrequencies of FAS-1377A/G between the recurrence and non-recurrence(P=0.01); The FAS-1377AA genotype and the combined GA+AA genotypeexhibited a higher recurrence than the GG genotype (HR=1.7095%CI=1.18~2.43).3.2The genotype frequencies of the FAS-670G/G+G/A and A/A in alives anddeaths were49.6%,50.4%å'Œ32.4%,67.6%, respectively. There wasstatistically significant difference in the genotype distributions or allelefrequencies of FAS-1377A/G between the alives and deaths (P=0.03);Compared to the A/A genotype, the GA+GG genotype exhibited a worsesurvival (HR=1.7095%CI=1.18~2.43). The genotype frequencies of theFAS-670A/Aå'ŒA/G+G/G in recurrence and non-recurrence were52.2%,47.8%å'Œ37.9%,62.1%, respectively. There was statistically significantdifference in the genotype distributions or allele frequencies of FAS-670G/Agenotype and the combined GA+GG genotype exhibited a higher recurrencethan the AA genotype (HR=1.4495%CI=1.00~2.07).3.3The genotype frequencies of the FASL-844T/T,T/C,C/C in alives anddeaths were4.2%,32.8%,63%å'Œ8.1%,33.8%,58.1%, respectively. Therewas no statistically significant difference in the genotype distributions or allelefrequencies of FASL-844T/C between the alives and deaths (P>0.05);Thegenotype frequencies of the FASL-844T/T,T/C,C/C in recurrence andnon-recurrence were7.3%,33.1%,59.7%å'Œ2.9%,33.3%,63.8%, respectively.There was no statistically significant difference in the genotype distributionsor allele frequencies of FASL-844T/C between the alives and deaths (P>0.05).4Association between the combined genotype of Fas and FasL SNP and riskof OC 4.1Combined the SNP in the FAS and FASL gene suggest the presence ofboth FASL–844TT/TC and FAS–1377GG genotypes was associated withan even lower risk for ECO compared with FASL844CC and FAS-1377GGgenotypes(OR=0.521(0.322~0.841);OR=0.311(0.105~0.9)).4.2Combined the SNP in the FAS and FASL gene suggest the presence ofboth FASL–844TT/TC and FAS–670AA genotypes was associated with aneven lower risk for ECO compared with FASL844CC and FAS-670AAgenotypes(OR=0.236(0.073~0.761); OR=0.563(0.335~0.947)).Conclusions:1FAS-1377G/A SNP did not significantly affect the susceptibility to EOC.2FAS-670A/G SNP did not significantly affect the susceptibility to EOC.3FASL-844T/C SNP was associated with susceptibility to epithelial ovariancancerï¼›carrying T allele may significantly decrease the risk of developingepithelial ovarian cancer.4FAS-1377G/A SNP was associated with survival and recurrence toepithelial ovarian cancer, carrying A allele may exhibited a worse survival andhigher recurrence than GG genetype.5FAS-670A/G SNP was associated with survival and recurrence to epithelialovarian cancer, carrying G allele maybe exhibited a worse survival and higherrecurrence than AA gene type.6FASL-844T/C SNP did not significantly affect survival and recurrence toepithelial ovarian cancer.7FAS and FASL SNP combined genotype may significantly decrease the riskof developing epithelial ovarian cancer. |
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