| Objective: To analyze the distribution of KIR genes and the association of KIR genes polymorphism on nasopharyngeal carcinoma development;To explore the correlation between KIR/HLA interactions and nasopharyngeal carcinoma chemotherapy sensitivity,so as to evaluation the application value of immunogenetics in NPC treatment and prognosis.Furthermore,provide the new evidences for nasopharyngeal carcinoma pharmacogenomics study.Methods: The expression of KIR gene was detected by polymerase chain reaction / sequence specific primer(PCR-SSP)and SYBER Green Ⅰ real-time fluorescent PCR in 204 patients with nasopharyngeal carcinoma and 201 healthy controls.Sequencing-based typing were conducted for KIR2DS4 and HLA-A genes.100 patients who used induction chemotherapy combined with concurrent chemoradiotherapy were collected,and the side effects and chemosensitivity of chemotherapy in the process of treatment were counted.The genetic polymorphism differences between nasopharyngeal carcinoma case group and healthy control group were compared from three aspects: KIR gene,KIR haplotype,HLA-A ligand and KIR-HLA combination,and the correlation among them and the side effects of chemotherapy in the process of induction chemotherapy was analyzed.Results: The correlation between KIR、HLA and their interaction and the pathogenesis of nasopharyngeal carcinoma was studied by case-control method.The results are as follows: 1.A total of 15 known KIR genes were detected in 204 patients with nasopharyngeal carcinoma and 201 healthy controls.In all 405 individuals detected,the frame genes KIR3DL2、3DL3 and 2DL4 existed in all subjects,and the detection frequency was 100%;2.The expression of activating KIR2DS4(97.55% vs 91.54%,OR=3.677,95%CI=1.320~10.168,P=0.008)and inhibitory KIR3DL1(97.55% vs 93.03%,OR=2.980,95%CI=1.053~8.434,P=0.032)in the NPC case group was significantly higher than that in the control group;3.A total of 50 KIR haplotypes,AA,AB and BX,were detected in 204 NPC patients and 201 healthy controls.Among BX haplotype combinations,the detection frequency of BB haplotype in NPC patients was significantly lower than that in healthy group(4.90% vs 11.44%,OR=0.399,95%CI=0.185~0.861,P=0.016);4.Four alleles of KIR2DS4*00101,*010,*003 and *004 were detected in the case group;Five alleles of 2DS4*00101,*010,*003,*004 and *014 were detected in the healthy control group.5.After HLA-A genotyping,the HLA-A results of 204 NPC cases and 184 healthy controls were obtained,and a total of 28 HLA-A ligands were detected.The detection frequency of HLA-A * 11:01 in NPC case group was significantly lower than that in healthy control group(23.53% vs 30.71%,OR=0.694,95%CI=0.505~0.955,P=0.024),and the detection frequency of HLA-A * 02:07 was significantly higher than that in healthy control group(17.16% vs 8.70%,OR=2.175,95%CI=1.394~3.392,P=0.000);The patients were divided into two groups according to whether they were sensitive to chemotherapy and whether the toxic and side effects of chemotherapy occurred.The differences in the expression of KIR gene / haplotype,ligand HLA and KIR + HLA combination between the two groups were analyzed to explore the correlation.The results are as follows: 1.A total of 110 eligible patients with nasopharyngeal carcinoma were collected,including 37 cases(33.64%)in platinum chemotherapeutic drug sensitive group(CR+PR)and 73 cases(66.36%)in chemotherapy insensitive group(SD + PD).The toxic and side effects of 110 patients with nasopharyngeal carcinoma were collected.The blood toxic and side effects included leucopenia in 58 cases(52.73%),erythropenia in 38 cases(35.45%),neutropenia in 52 cases(47.27%)and bone marrow suppression in 71 cases(64.55%);Non-Hematological toxic and side effects,gastrointestinal reactions in 92 cases(83.64%),renal function injury in 22 case(20.00%);2.The chemotherapy sensitivity of nasopharyngeal carcinoma patients with HLA-A*02:07 was 3.760 times higher than that of nasopharyngeal carcinoma patients without HLA-A*02:07(51.35% vs 21.91%,OR=3.760,95%CI=1.552~8.648,P=0.002);3.The number of KIR genes is significantly correlated with the occurrence of neutropenia: the incidence of neutropenia is significantly higher in individuals with 3-5 activating KIR genes than those who carry 1-2 activating KIR genes of individuals(55.77% vs 44.23%,OR=2.222,95%CI=1.033-4.777,P=0.04);the incidence of neutropenia was significantly lower in individuals carrying 8 inhibitory KIR genes than 6-7 inhibitory KIR genes(30.77% vs 69.23%,OR=2.852,95%CI=1.375-10.789,P=0.008);4.There is no correlation between KIR haplotype and chemotherapy side effects,but in neutropenia,the incidence of Bx haplotype is higher than that of AA haplotype.(63.26% vs 36.54%,OR=0.458,95%CI=0.218~1.006,P=0.0504);5.In the associated correlation of KIR2DS4 alleles and platinum drug chemotherapy,the incidence of red blood cell reduction in NPC patients carrying KIR2DS4 * 003 was significantly lower than that of NPC patients without carrying the allele;(2.63% vs 97.37%,OR=0.135,95%CI=0.017~1.082,P=0.032);6.The incidence of neutral granulocyte reduction occurs in patients with activated KIR2DS3 and inhibitory 2DL5,which is significantly higher than those who do not carry the gene;(38.46% vs 20.69%,OR=2.396,95%CI=1.028~5.583,P=0.040;55.77% vs 36.21%,OR=2.222,95%CI=1.033~4.777,P=0.040);Conclusion: 1.KIR2DS4 and 3DL1 may be associated with NPC;2.There is a 22 bp deletion of 2DS4*010 allele in exon 5 of KIR2DS4,which is associated with nasopharyngeal carcinoma;3.HLA-A*11:01 may be the protective gene of nasopharyngeal carcinoma,while HLA-A*02:07 is the disease gene of nasopharyngealcarcinoma;4.Nasopharyngeal carcinoma patients with HLA-A*02:07 genotype are highly sensitive to platinum-based chemotherapy drugs,suggesting that HLA may as a marker gene for tumor chemosensitivity;5.Carrying more activated KIR genes or less inhibitory KIR genes,and carrying KIR2DL5 and KIR2DS3 are the susceptible factors of neutropenia in patients with nasopharyngeal carcinoma during platinum chemotherapy,suggesting that KIR can be used as a predictor of the toxic and side effects of tumor chemotherapy. |
PDF Full Text Request