The Value Study Of PD-L1 Expression And Gene Polymorphism Of The Diagnosis And Prognosis In Gastric Cancer

Background and objectiveGastric cancer(GC)is one of the most common fatal cancers,The incidence for gastric carcinoma has had a recent increase.Effective methods for early diagnosis,monitoring metastasis,and prognosis are currently unavailable for gastric cancer.Immunotherapy has shown bright promise in the treatment of gastric cancer.Unfortunately,it was reported that gastric cancer cells can escape immune surveillance by a variety of mechanisms which prevent the immune system from producing effective antitumor immune responses.Some studies have reported that PD-L1 increases apoptosis of antigen-specific human T-cell clones and inhibits the activation of CD4 and CD8 T-cells in vitro.Moreover PD-L1 high expression in the multiple tumor,including gastric cancer.Several studies have shown that PD-1 or PD-L1 antibodies could relieve the inhibitory effects of PD-L1 on cytotoxic T-cells and hence accelerate the removal of tumor cells by cytotoxic T-cells and interrupting the PD1/PD-L1 signal pathway is a promising therapeutic strategy for cancer.Apurinic/apyrimidinic endonuclease 1(APE1)plays an important role in multiple biological processes.It can repair DNA damage and suppress tumorigenesis through maintaining genome stability.APE1,as a redox-active protein,also activates many transcription factors.APE1 overexpression enhanced the tumorigenesis of gastric cancer.SNP is one of the important factors for cancer susceptibility.Several polymorphisms in exons of PD-L1 have been described and related with autoimmune diseases.However,the SNP of PD-L1 for gastric cancer also rarely reported.In part one,we detected the association between the expression of PD-L1 and APE1 with the gastric cancer patients with 107 cases.And then The PCR-CTPP was conducted to analyze the associations of gastric cancer susceptibility with PD-L1 gene single nucleotide polymorphism.To provide theoretical support for the PD-L1 as a target in immune therapeutic of gastric cancer,MethodsThis program consisted of two parts.In the part one,the expression of PD-L1 and APE1 in 107 gastric cancer tissues were evaluated by IHC.Observe the expression of these two genes in gastric carcinoma,and to analyze the correlation of their expression and clinical case characteristics and prognosis.In the second parts,a total of 242 genetically unrelated subjects including 141 healthy controls and 101 gastric cancer patients participated in this study.The genotypes of the rs4143185 were determined using sequencing technology(Invitrogen,Shanghai,China).And the genotypes of the rs2890658 and rs17718883 were determined using PCR-RFLP.To Analysis the correlation between the single nucleotide polymorphisms of PD-L1 and the susceptibility and prognosis of gastric cancer.All data using EXCEL spreadsheet registration,collect;using SPSS 19.0 software for statistical analysis of the data collected.Results107 cases of gastric cancer tissues,The percentage of PD-L1-positive cells in gastric carcinoma was 50.5%(54/107).About 86.9%(93/107)of gastric carcinoma tissues showed positive APE1 immunostaining.PD-L1 staining was significantly correlated to the depth of invasion(odds ratio [OR] =3.37;P=0.005),lymph node metastasis(OR =2.68;P=0.020),tumor differentiation(OR =3.19;P=0.008)and pathological type(?2=8.676;P=0.013).Moreover,the positive rate of PD-L1 expression is much higher in high differentiation,lymph node metastasis,and higher T stage than that in others.PD-L1-positive gastric cancers were significantly associated with a poor prognosis(P<0.05)APE1 expression in gastric cancer cells was significantly correlated to lymph node metastasis(OR =3.26;P=0.037),depth of invasion(OR =7.61;P=0.001),and survival time(OR =10.91;P=0.040).APE1 positive expression was a marker of poor prognosis in gastric cancer patients(P=0.035).49.5%(53/107)of gastric cancer tissues demonstrated both APE1 and PD-L1 positive expression.Spearman's rank correlation analysis showed that APE1 and PD-L1 expression in gastric cancer were positively correlated(r=0.336,P<0.01).PD-L1 and APE1 co-positivity was significantly related to a poor prognosis(P=0.003).Tumor location,depth of invasion,lymph node metastasis,tumor differentiation,and pathological type were significantly correlated to OS(P<0.05).The median survival time of patients with cancers of the cardia was 22±2.42 months,which was shorter than that of gastric body cancers(45±3.86 months,P=0.003).The median survival time of tubular adenocarcinoma was 41.0 months,while the median survival time of poorly differentiated carcinoma was 20±2.24 months(P=0.004).The depth of invasion was a significant prognostic factor(risk ratio 19.91;95% confidence interval: 4.83–82.03;P=0.000).The subjects carrying the rs17718883 CG genotype or CG+GG genotype showed a lower risk than subjects carrying the CC genotype(Adjusted OR=0.238;95%CI: 0.12~0.49;P<0.001 for CG;Adjusted OR=0.196;95%CI: 0.10~0.38;P<0.001 for CG+GG).Carriers of rs17718883 G allele showed a significantly decrease of gastric cancer risk than C allele(Adjusted OR: OR=0.210;95%CI: 0.12~0.38;P<0.001).The CC genotype and CG genotype of rs17718883 locus,the median survival time was: 22 months,56 months;the difference was statistically significant(P=0.009);the median survival time of CG+GG genotype was 56 months,(CC vs.CG+GG;P=0.014).COX regression model was used to analyze rs17718883 locus we found that the mutant genotype site were favorable factors for the OS,CG(HR: 0.229,P = 0.006)CG + GG(HR: 0.266,P = 0.007)difference statistical significance,GG(HR: 0.984,P = 0.988)difference was not statistically significant.ConclusionsPart one:1.The PD-L1 expression and APE1 are increased in gastric cancer.There was a significant difference in the positive expression of PD-L1 and APE1 with the depth of invasion,lymph node metastasis,histological type and overall survival time in gastric cancer.2.The positive expression of PD-L1 and APE1 have poor prognosis compared with the negative expressions in tissue of patients with gastric cancer.3.APE1 and PD-L1 expression in gastric cancer were positively correlated.There might be some values to detect both PD-L1 and APE1 in the diagnosis and prognosis of gastric cancer?Part two:1.The subjects carrying the rs17718883 mutation genotype have significantly associated with gastric cancer susceptibility,Carriers of rs17718883 G allele showed a significantly decrease of gastric cancer risk than C allele.2.The subjects carrying the rs17718883 CG heterozygous mutation genotype can let patients get better prognosis;GG genotype can decreased the risk of gastric cancer,but haven't better OS.