IDH1突变对替莫唑胺化疗治疗脑胶质瘤患者的临床疗效及其对免疫细胞因子、预后的影响

Clinical efficacy of IDH 1 mutation in temozolomide chemotherapy for glioma patients and its impact on immune cytokines and prognosis

目的:研究异柠檬酸脱氢酶1(IDH1)突变对替莫唑胺化疗治疗脑胶质瘤患者的临床疗效及其对免疫细胞因子、预后的影响。方法:选取2021年10月至2022年10月苏州大学附属独墅湖医院手术切除且经病理证实的脑胶质瘤患者134例作为研究对象,直接测序法测定IDH1突变情况,免疫组化测定脑胶质瘤组织IDH1表达。脑胶质瘤患者均进行替莫唑胺化疗,分析IDH1突变对替莫唑胺化疗治疗脑胶质瘤临床疗效、免疫细胞因子(IFN-γ、IL-2、IL-4、IL-10)及预后生存状态的影响。结果:134例脑胶质瘤组织中79例存在IDH1突变,突变位点多为R132,突变率为58.96%,显著高于正常脑组织(χ^(2)=48.066,P<0.05)。免疫组化显示,134例脑胶质瘤组织中56例IDH1强阳性表达。IDH1突变型组WHO分级Ⅳ级占比低于IDHI野生型组[11.39%(9/79) vs 63.64%(35/55),Z=41.020,P<0.05],IDH1突变型组低分化比例高于IDHI野生型组[50.63%(40/79) vs 20.00%(11/55),χ^(2)=12.907,P<0.05]。IDH1突变型组总有效率高于IDH1野生型组[91.14%(72/79) vs 76.36%(42/55),χ^(2)=5.575,P<0.05]。IDH1突变型组IFN-γ、IL-2水平高于IDH1野生型组[(28.98±3.25) pg/ml vs (20.15±2.54) pg/ml、(33.42±4.25) pg/ml vs (25.23±3.52) pg/ml,t=16.870、11.750, P<0.05],IL-4、IL-10水平低于IDH1野生型组[(7.90±1.02) pg/ml vs(12.38±1.66) pg/ml、(8.79±1.00) pg/ml vs (15.26±1.23) pg/ml,t=19.330、33.500,P<0.05]。IDH1突变与替莫唑胺化疗后IFN-γ、IL-2水平呈正相关(r=0.845、0.772,P<0.05),与替莫唑胺化疗后IL-4、IL-10水平呈负相关(r=-0.786、-0.685,P<0.05)。IDH1突变型组替莫唑胺化疗后生存率高于IDH1野生型组[89.87%(71/79) vs 72.70%(40/55),Log Rank检验χ^(2)=5.208,P<0.05]。Cox回归分析发现,WHO分级Ⅲ级(RR=1.342)、低分化(RR=1.783)、IFN-γ(RR=1.808)、IL-2(RR=2.112)、IL-4(RR=2.342)、IL-10(RR=1.342)为危险因素,替莫唑胺化疗有效(RR=0.653)、IDH1突变(RR=0.895)为保护因素,影响脑胶质瘤患者替莫唑胺化疗预后(P<0.05)。结论:IDH1突变与脑胶质瘤患者疾病分级、分化程度有关,可影响替莫唑胺化疗疗效、免疫细胞因子表达,是替莫唑胺化疗后预后生存的保护因素。

Objective:To study clinical efficacy of isocitrate dehydrogenase 1(IDH1)mutation on temozolomide chemotherapy for glioma patients and its impact on immune cytokines and prognosis.Methods:A total of 134 patients with glioma who underwent surgical resection and were confirmed by pathology in Dushu Lake Hospital Affiliated to Soochow University from October 2021 to October 2022 were selected as research subjects.IDH1 mutation status was measured by direct sequencing method,and IDH1 expres-sion rate in glioma tissue was determined by immunohistochemistry.All patients with brain glioma were treated with temozolomide chemotherapy.Effects of IDH1 mutation on clinical efficacy,immune cytokines(IFN-γ,IL-2,IL-4,IL-10)and prognosis of glioma were analyzed.Results:Seventy-nine cases out of 134 cases of glioma tissue had IDH1 mutations,mostly at R132,with a mutation rate of 58.96%,significantly higher than normal brain tissue(χ^(2)=48.066,P<0.05).Immunohistochemistry showed strong positive expression of IDH1 in 56 out of 134 glioma tissues.Proportion of WHO gradeⅣin IDH1 mutant group was lower than IDHI wild type group[11.39%(9/79)vs 63.64%(35/55),Z=41.020,P<0.05].Proportion of low differentiation in IDH1 mutant group was higher than IDHI wild type group[50.63%(40/79)vs 20.00%(11/55),χ^(2)=12.907,P<0.05].Total effective rate in IDH1 mutant group was higher than IDH1 wild type group[91.14%(72/79)vs 76.36%(42/55),χ^(2)=5.575,P<0.05],IFN-γand IL-2 levels were higher than IDH1 wild type group[(28.98±3.25)pg/ml vs(20.15±2.54)pg/ml,(33.42±4.25)pg/ml vs(25.23±3.52)pg/ml,t=16.870,11.750,P<0.05],IL-4 and IL-10 levels were lower than IDH1 wild type group[(7.90±1.02)pg/ml vs(12.38±1.66)pg/ml,(8.79±1.00)pg/ml vs(15.26±1.23)pg/ml,t=19.330,33.500,P<0.05].IDH1 mutation was positively correlated with IFN-γand IL-2 levels after temozolo-mide chemotherapy(r=0.845,0.772,P<0.05),and negatively correlated with IL-4 and IL-10 levels after temozolomide chemotherapy(r=-0.786,-0.685,P<0.05).Survival rate after chemotherapy in IDH1 mutant group was higher than IDH1 wild type group[89.87%(71/79)vs 72.70%(40/55),Log Rank testχ^(2)=5.208,P<0.05].Cox regression analysis found that WHO gradeⅢ(RR=1.342),poorly differentiated(RR=1.783),IFN-γ(RR=1.808),IL-2(RR=2.112),IL-4(RR=2.342),IL-10(RR=1.342)as risk factors,temozolo-mide chemotherapy efficacy(RR=0.653),IDH1 mutation(RR=0.895)as protective factors affect prognosis of temozolomide chemo-therapy in glioma patients(P<0.05).Conclusion:IDH1 mutation is related to disease grade and differentiation degree of glioma patients,and can affect efficacy of temozolomide chemotherapy and expressions of immune cytokines,which is a protective factor for prognosis and survival after temozolomide chemotherapy.