| Background: Gastric cancer is one of the most common malignancies in China.Acorrding to The Status and Trends of Tumors in China 2017 published by the National Cancer Center: The incidence of GC ranks second among Chinese male patients and fourth among female patients,and GC remains the second leading causes of cancer-related death in China.Because of the deficiency of early gastric cancer screening system,gastric cancer is usually diagnosed at an advanced stage in China.Chemotherapy-led multimodality therapy model is still the main treatment for advanced gastric cancer,but the prognosis of the patients with advanced gastric cancer is poor,median survival time has not yet exceeded 1 year.Single nucleotide polymorphism(SNP)is defined as an DNA sequence polymorphism caused by a single nucleotide mutation,which can better reflect the differences between individuals and populations,it has the characteristics of high frequency of mutation,wide distribution,stable Genetic and mature detection technology,has become the main research methods in pharmacogenomics.It has a wide distribution,high frequency of mutation,stable Genetic and detection technology is mature,has become the main research methods in pharmacogenomics.Many studies have reported that the PI3K/PTEN/Akt/mTOR signaling pathway plays an important role in the process of tumorigenesis,invasion and metastasis.However,There is rare research about the relationship between PI3K/PTEN/Akt/mTOR signaling pathway gene single nucleotideand the status of gastric cancer chemotherapy efficacy and survival prognosis at home and abroad.Objective:This research is designed to investigate the association of PI3K/PTEN/Akt/mTOR signaling pathway single nucleotide polymorphism with first-line chemotherapy in advanced gastric cancer by detecting the polymorphism of 20 SNP locis in PI3K、PTEN、Akt、mTOR.Methods:The pathological specimens and clinical data of 82 patients with advanced gastric cancer who received first-line chemotherapy from 2010.1 to 2016.5 in the second hospital of Dalian Medical University were collected,then we test the genetic polymorphism of each loci by SNaPshot sequencing,The correlation among clinicopathological features、chemotherapy regimen and chemotherapy efficacy、disease control rate was analyzed by χ2 test or Fisher exact test,and correlation among clinicopathological features、chemotherapy regimen and PFS、OS was analyzed by Log Rank test,P <0.05 for the difference was statistically significant,survival curve was drawn by using Kaplan-Meier method.the gene polymorphism of each locus and efficiency of chemotherapy、disease control rate were analyzed by Logistic regression analysis,and calculated the OR and 95%CI,the gene polymorphism of each locus and PFS、OS were analyzed by Kaplan-Meier method and COX regression analysis,P <0.05 for the difference was statistically significant,survival curve was drawn by using Kaplan-Meier method,all the data are analyzing by SPSS22.0.Result:1、PIK3CA rs3729679、rs7651265、rs7640662、rs7621329、rs2459693,PTEN rs2835343、rs701848、rs17431184、rs12569998,Akt1 rs2498804、rs1130214、rs2494732、rs2494752、rs2498786、rs3803304,Akt2 rs62107593、rs34716810 and mTOR rs7212142、rs11121704、rs1064261 those 20 gene frequency distribution of SNPs were in accordance with Hardy-Weinberg equilibrium(P<0.05);PIK3CA rs6443624、rs2699887,PTEN rs2299939,Akt1 rs1130233、rs38033007 and mTOR rs2295080、rs1062935 those 7 gene frequency distribution of SNPs improper with Hardy-Weinberg equilibrium(P<0.05).2、Patients with platinum-based chemotherapy had higher DCR than those without chemotherapy(84.6% and 62.8%,P=0.026);Patients with platinum-based chemotherapy had better PFS than those without chemotherapy(6.0 and 4.0 months,P=0.004);Patients with infiltration depth T1 and T2 were significantly higher than those with T3 and T4(16.0 and 11.0 months,P = 0.023);Patients who was diagnosed as adenocarcinoma had significantly higher OS than those with other pathologic types(12.0 and 8.0 months,P = 0.007);Patients with low differentiation was significantly lower than that of the patients with moderate and high differentiation(10.5 and 14.0months,P = 0.044)。3、In 82 patients with advanced GC who received first-line chemotherapy:(1)PIK3CA rs2459693 CC genotype had better PFS than CT+TT genotype(6.0and 4.0 months,P=0.029),multivariate analysis showed that the risk of disease progression in patients with CT+TT genotype was 1.954 times higher than that in CC genotype,it could be used as an independent prognostic factor for PFS in patients with advanced gastric cancer after correction(P=0.040,HR=1.954,95%CI=1.032-3.699).(2)PTEN rs17431184 CC genotype had significantly shorter PFS than CT+TT genotype(2.0 and 5.0 months,P=0.020),multivariate analysis showed that the risk of disease progression in CC genotype is 3.740 times higher than that in CT+TT genotype,it could be used as an independent prognostic factor for PFS in patients with advanced gastric cancer(P=0.024,HR=3.740,95%CI=1.186-11.792).(3)Akt1 rs2494752 AA genotype had lower DCR than GG+GA genotype(64.3%and 84.6%,P=0.042),multivariate analysis showed that it could be used as an independent factor for DCR in patients with advanced gastric cancer after correction(P=0.009,OR=5.578,95%CI=1.538-20.225);And disease control rate was significantly lower in patients with the A allele than in the G allele(69.5% and 86.4%,P = 0.029).(4)Akt2 rs34716810 AA genotype had significantly shorter OS than GG+GA genotype(6.0 and 12.0 months,P=0.033),multivariate analysis showed that the risk of death in patients with AA genotype was 5.603 times higher than that in GG+GAgenotype,it could be used as an independent prognostic factor for PFS in patients with advanced gastric cancer after correction(P=0.001,HR=5.603,95%CI=2.005-15.657).4、In 39 patients with platinum-containing chemotherapy:Akt2 rs34716810 AA genotype had significantly shorter PFS than GG+GA genotype(1.0 and 6.0 months,P=0.009),multivariate analysis showed that the risk of disease progression in patients with AA genotype is 9.594 times higher than that in GG+GA genotype,it could be used as an independent prognostic factor for PFS in patients with advanced gastric cancer who received platinum-containing first-line chemotherapy after correction(P=0.027,HR=9.594,95%CI=1.286-71.585).5、In 39 patients with paclitaxel-containing chemotherapy:(1)Akt1 rs2494752 in the co-dominant model(AA/GA/GG),GA genotype had significantly higher DCR than AA genotype(92.3% and 52.3%,P=0.034),multivariate analysis showed that it could be used as an independent factor for DCR in patients with advanced gastric cancer who received paclitaxel-containing first-line chemotherapy after correction(P=0.026,OR=53.146,95%CI=1.604-1760.954);In the dominant model(AA/GA+GG),AA genotype had significantly lower DCR than GG+GA genotype(52.3% and 94.1%,P=0.017),multivariate analysis showed that it could be used as an independent factor for DCR in patients with advanced gastric cancer who received paclitaxel-containing first-line chemotherapy after correction(P=0.020,OR=62.255,95%CI=1.912-2027.069);And Patients with A allele had significantly lower DCR than patients with G allele(61.8% and 95.2%,P=0.004);(2)Akt1 rs2494752 GG genotype had significantly longer PFS than AA+GA genotype(7.5 and 4.0 months,P=0.032),multivariate analysis showed that the risk of disease progression in patients with GG genotype is 0.168 times higher than that in AA+GA genotype,it could be used as an independent prognostic factor for PFS in patients with advanced gastric cancer who received paclitaxel-containing first-line chemotherapy after correction(P=0.021,HR=0.168,95%CI=0.037-0.762).(3)Akt2 rs34716810 in the co-dominant model(GG/GA/AA),GG genotype had significantly longer OS than AA genotype(10.0 and 4.0 months,P=0.001),multivariate analysis showed that the risk of death in patients with AA genotype was7.926 times higher than that in GG genotype,it could be used as an independent prognostic factor for OS in patients with advanced gastric cancer who received paclitaxel-containing first-line chemotherapy after correction(P=0.005,HR=7.926,95%CI=1.793-26.063);In the hidden model(AA/GG+GA),AA genotype had significantly shorter OS than GG+GA genotype(4.0 and 12.5 months,P=0.001),multivariate analysis showed that the risk of death in patients with AA genotype was7.247 times higher than that in GG+GA genotype,it could be used as an independent prognostic factor for OS in patients with advanced gastric cancer who received paclitaxel-containing first-line chemotherapy after correction(P=0.004,HR=7.247,95%CI=1.907-27.540).Conclusion:1、The gene polymorphism of PIK3 CA rs2459693、 PTEN rs17431184 、Akt1rs2494752 and Akt2 rs34716810 are expected to be molecular markers for predicting the first-line chemotherapeutic efficacy and prognosis of advanced gastric cancer.2、The gene polymorphism of Akt2 rs34716810 is expected to be a molecular marker for predicting the first-line chemotherapy efficacy of platinum-containing regimen in advanced gastric cancer.3、The gene polymorphism of Akt1 rs2494752 and Akt2 rs34716810 are expected to be molecular markers for predicting the first-line chemotherapeutic efficacy and prognosis of paclitaxel-containing regimen in advanced gastric cancer. |
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