Single Nucleotide Polymorphisms Of NRP1 And Related Genes Are Associated With First-line Chemotherapy For Advanced Gastric Cancer

Background and PurposeGastric cancer is the most common malignant digestive tumor in China,whose morbidity and mortality rank the second place among malignant tumors.NRP-1 is an important typeⅠtransmembrane protein involved in the development and progression of tumors,which is involved in the biological activities with regulation of tumors mainly through three pathways: the VEGF-VEGFR2 pathway,the PDGF-PDGFR pathway and NRP-1-ABL pathway.The newly found biological effects that it is involved in include the promotion of development and progression of tumors,the promotion ofneogenesis of tumor angiogenesis,the promotion of metastasis and invasion of tumors and its participation of the regulation of tumor sensitivity to chemotherapy drugs.Single nucleotide polymorphism is a third generation genetic marker,which refers to the DNA polymorphism generated by a single nucleotide mutation and can directly affect the expression and function of protein,with genetic stability,wide distribution,easy statistics and Analysis,suitability for large-scale screening andother advantages.Studies have shown that genetic factors play a significant role in gastric cancer.However,current SNP studies related to gastric cancer still focus on the susceptibility of disease,and there is still a lack of research in the resistance of chemotherapy in advanced gastric cancer.This study intends to analyze the relationship between NRP-1 and the SNP of some genes in the involving pathway and the treatment of advanced gastric cancer from the DNA level in combination with the problems encountered in advanced gastric cancer and the latest technical measures,hoping to provide possible signs for the prediction of prediction of sensitivity to chemotherapy and so on for the purpose of individualized therapy and in the meantime provide a basis for the further study of drug resistance mechanism and toxicity mechanism in chemotherapy.Materials and MethodsSelecting the patients with advanced gastric cancer and chemotherapy who were newly diagnosed at the Second Affiliated Hospital of XXXX University from January 2010 to May2016,with their pathologic paraffin samples removed and DNA extracted by using QIAamp DNA FFPE Tissue Kit.Selecting the label SNP locus of the target genes from the public SNP database of 1000 genome projects in NCBI,screenedaccording to the location and previous literature and detected by theSNaPshot method to determine the gene polymorphism.Collecting the clinical information of patients according to their clinical data and further improving the relevant information through clinical follow-up and telephone follow-up;evaluating the efficacy of chemotherapy by using the RECIST criteria andfor the difference in clinical data of each group of patients,adopting the SPSS 22.0 statistical software to analyze the frequency of polymorphism at each locus and calculating the distribution of polymorphism in gastric cancer;Using the chi-square test of R*C table for comparison of constituent ratio,adopting unconditional logistic regression analysis for the relationship between genotype and disease progression and calculating OR value and 95% CI;Based on the wild type of each locus,making comparison between heterozygous and mutant with wild type with unconditional logistic regression;adopting theKapan-Meier method to draw the survival curves and verifying by Log Rank.ResultsOf the 82 patients,58(70.7%)are male and 24(29.3%)are female,which relatively accords with the feature that incidence of gastric cancer for male is higher than that of female.The medium age of patients was 60.There were 54(65.9%)poorly differentiated patients and28 moderately differentiated patients(34.1%).There are 79 patients with T staging identified,including 612(8%)T1-2 patients and 73(92%)T3-4 patients.Logistic regression analysis indicates that CT genotype of KDR gene on RS7692791 F locus is a dangerous factor of progressive disease.The risk of progressive disease for patients carrying with CT genotype is higher than patients carrying with TT genotype(OR=3.798,95%CI=1.061-13.587,P=0.040).Under the dominance model(TT/CT+CC),genotype has the correlation with progressive disease(OR=3.491,95%CI=1.013-12.029,P=0.048),but gene polymorphism in each locus has no correlation with progressive disease(P>0.05).Survival analysis shows that in the dominance model of KDR gene at RS2305948 locus(CC/CT+TT),wild pure type CC has the longer PFS(5 months/2.5 months).The difference has statistical difference(x2=4.268,P=0.039).In the recessive model of NRP-1 gene atRS2273466(AA+ GA/GG),pure mutation GG has the shorter PFS(4.5 months/1.5 months)and the difference has statistical significance(x2=5.643,P=0.018).、Conclusions:1.CT genotype of KDR gene at rs7692791 locus is a dangerous factor of progressive disease.First-line chemotherapy effect of wild type is better than mutation type.22..RS2305948 locus of KDR gene and genotype of NRP-1 at RS2273466 locus have an obvious significance on PFS of patients,but PFS of wild type is longer than mutation type.