异柠檬酸脱氢酶1基因R132H突变与胶质瘤相关性癫痫患者术后痫性再发的关系
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摘要
目的检测胶质瘤相关性癫痫患者肿瘤组织中异柠檬酸脱氢酶1(IDH1)R132H基因突变情况,并探讨该突变与患者术后痫性再发的关系。方法应用免疫组化法检测90例患者肿瘤组织IDH1R132H突变,建立Cox多因素回归模型分析该突变与患者术后痫性再发的关系。结果 90例患者有32例突变,突变率为35.6%;突变主要发生在Ⅱ、Ⅲ级胶质瘤中;肿瘤组织病理分型中突变以弥漫性星形细胞瘤和间变性星形细胞瘤居多;该突变在胶质瘤术后复发患者及术后服用较多数量抗癫痫药患者中所占比例大,且差异均有统计学意义(P <0.05)。患者术后1年内痫性再发率为42.2%(38/90),突变在术后痫性再发组与未发组间差异有统计学意义(χ~2=21.869,P <0.001)。Cox多因素回归提示肿瘤位于颞叶(HR=3.197,95%CI:1.527～6.693)、肿瘤术后复发(HR=10.328,95%CI:3.636～29.339)以及IDH1 R132H突变(HR=3.169,95%CI:1.234～8.412)是患者术后痫性再发的独立危险因素(均P <0.05)。结论 IDH1R132H突变对胶质瘤相关性癫痫患者术后1年内癫痫再发的控制可能有不利影响。对此类患者需采取更为严格的综合治疗措施以减少术后痫性发作,提高其生存质量。
Objective To detect the gene mutation of isocitrate dehydrogenase 1(IDH1)R132 H in tumor tissues of patients with glioma-related epilepsy,and to explore the relationship between this mutation and postoperative seizure recurrence in patients. Methods Immunohistochemistry was used to detect the IDH1 R132 H mutation in 90 patients,and the Cox multivariate regression model was established to analyze the relationship between the mutation and postoperative seizure recurrence. Results There were 32 mutations in 90 patients,and the mutation rate was 35.6%;Mutations mainly occurred in grade Ⅱ and Ⅲ gliomas;and in diffuse astrocytoma and anaplastic astrocytoma;The mutation accounted for a large proportion of patients with recurrence after glioma surgery and patients taking more antiepileptic drugs after surgery,and the difference was statistically significant(P < 0.05).The rate of epileptic recurrence was 42.2%(38/90)within 1 year after surgery. The difference between the mutation in the postoperative seizure recurrence group and the unexposed group was statistically significant(χ~2= 21.869,P < 0.001). Cox multivariate regression indicated that the tumor locating in temporal lobe(HR = 3.197,95%CI:1.527 ～ 6.693),tumor recurrence(HR = 10.328,95%CI:3.636～29.339)and IDH1 R132 H mutation(HR =3.169,95%CI:1.234～8.412)was an independent risk factor for postoperative seizure recurrence in patients(all P < 0.05). Conclusions The IDH1 R132 H mutation may have an adverse effect on the control of epileptic recurrence within 1 year after glioma-related epilepsy. More stringent comprehensive treatment measures are needed for such patients to reduce postoperative seizures and improve their quality of life.
Objective To detect the gene mutation of isocitrate dehydrogenase 1(IDH1)R132 H in tumor tissues of patients with glioma-related epilepsy,and to explore the relationship between this mutation and postoperative seizure recurrence in patients. Methods Immunohistochemistry was used to detect the IDH1 R132 H mutation in 90 patients,and the Cox multivariate regression model was established to analyze the relationship between the mutation and postoperative seizure recurrence. Results There were 32 mutations in 90 patients,and the mutation rate was 35.6%;Mutations mainly occurred in grade Ⅱ and Ⅲ gliomas;and in diffuse astrocytoma and anaplastic astrocytoma;The mutation accounted for a large proportion of patients with recurrence after glioma surgery and patients taking more antiepileptic drugs after surgery,and the difference was statistically significant(P < 0.05).The rate of epileptic recurrence was 42.2%(38/90)within 1 year after surgery. The difference between the mutation in the postoperative seizure recurrence group and the unexposed group was statistically significant(χ~2= 21.869,P < 0.001). Cox multivariate regression indicated that the tumor locating in temporal lobe(HR = 3.197,95%CI:1.527 ～ 6.693),tumor recurrence(HR = 10.328,95%CI:3.636～29.339)and IDH1 R132 H mutation(HR =3.169,95%CI:1.234～8.412)was an independent risk factor for postoperative seizure recurrence in patients(all P < 0.05). Conclusions The IDH1 R132 H mutation may have an adverse effect on the control of epileptic recurrence within 1 year after glioma-related epilepsy. More stringent comprehensive treatment measures are needed for such patients to reduce postoperative seizures and improve their quality of life.
引文
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[14]李晓辉,王新军,杨如意,等.颞叶难治性癫痫患者致痫灶脑组织中HMGB1、TLR4表达及意义[J].实用医学杂志,2016,32(19):3223-3227.
[15]WINGKUN E C,AWAD I A,LUDERS H,et al.Natural history of recurrent seizures after resective surgery for epilepsy[J].Epilepsia,1991,32(6):851-856.
[16]杨卓,王新军,杨如意.胶质瘤相关性癫痫术后疗效及影响因素分析[J].中国神经精神疾病杂志,2017,43(4):220-224.
[17]HILDEBRAND J.Management of epileptic seizures[J].Curr Opin Oncol,2004,16(4):314-317.
[18]ZHONG Z,WANG Z,WANG Y,et al.IDH1/2 mutation is associated with seizure as an initial symptom in low-grade glioma:Areport of 311 Chinese adult glioma patients[J].Epilepsy Res,2015,109:100-105.
[19]DANG L,WHITE D W,GROSS S,et al.Cancer-associated IDH1mutations produce 2-hydroxyglutarate[J].Nature,2009,462(7274):739-744.
[20]KOLKER S,PAWLAK V,AHLEMEYER B,et al.NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria[J].Eur J Neurosci,2002,16(1):21-28.
[21]杨卓,王新军,单峤,等.胶质瘤相关性癫痫患者术后痫性再发的临床特征及影响因素[J].医学研究生学报,2017,30(4):405-408.2018-11-23
[2]PI X,CUI L,LIU A,et al.Investigation of prevalence,clinical characteristics and management of epilepsy in Yueyang city of China by a door-to-door survey[J].Epilepsy Res,2012,101(1-2):129-134.
[3]RHEIMS S,DUCRAY F,RYVLIN P.Choosing the tumoral epilepsy surgery candidate[J].Epilepsia,2013,54 Suppl 9:91-96.
[4]NEAL A,MOROKOFF A,O′BRIEN T J,et al.Postoperative seizure control in patients with tumor-associated epilepsy[J].Epilepsia,2016,57(11):1779-1788.
[5]MU L,XU W,LI Q,et al.IDH1R132H mutation is accompanied with malignant progression of paired primary-recurrent astrocytic tumours[J].J Cancer,2017,8(14):2704-2712.
[6]YAN H,PARSONS D W,JIN G,et al.IDH1 and IDH2 mutations in gliomas[J].N Engl J Med,2009,360(8):765-773.
[7]YANG Y,MAO Q,WANG X,et al.An analysis of 170 glioma patients and systematic review to investigate the association between IDH-1 mutations and preoperative glioma-related epilepsy[J].J Clin Neurosci,2016,31:56-62.
[8]CHEN H,JUDKINS J,THOMAS C,et al.Mutant IDH1 and seizures in patients with glioma[J].Neurology,2017,88(19):1805-1813.
[9]WANG Z F,CHEN H L.Relationship between IDH1 mutation and preoperative seizure in low-grade gliomas:A meta-analysis[J].Clin Neurol Neurosurg,2016,148:79-84.
[10]TOLEDO M,SARRIA-ESTRADA S,QUINTANA M,et al.Epileptic features and survival in glioblastomas presenting with seizures[J].Epilepsy Res,2017,130:1-6.
[11]谭国伟,陈曦,孙金莉,等.人脑胶质瘤IDH1基因突变与临床病理类别的关系[J].中华神经创伤外科电子杂志,2018,4(2):73-76.
[12]ZHAO S,LIN Y,XU W,et al.Glioma-derived mutations in IDH1dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha[J].Science,2009,324(5924):261-265.
[13]NEAL A,KWAN P,O′BRIEN T J,et al.IDH1 and IDH2 mutations in postoperative diffuse glioma-associated epilepsy[J].Epilepsy Behav,2018,78:30-36.
[14]李晓辉,王新军,杨如意,等.颞叶难治性癫痫患者致痫灶脑组织中HMGB1、TLR4表达及意义[J].实用医学杂志,2016,32(19):3223-3227.
[15]WINGKUN E C,AWAD I A,LUDERS H,et al.Natural history of recurrent seizures after resective surgery for epilepsy[J].Epilepsia,1991,32(6):851-856.
[16]杨卓,王新军,杨如意.胶质瘤相关性癫痫术后疗效及影响因素分析[J].中国神经精神疾病杂志,2017,43(4):220-224.
[17]HILDEBRAND J.Management of epileptic seizures[J].Curr Opin Oncol,2004,16(4):314-317.
[18]ZHONG Z,WANG Z,WANG Y,et al.IDH1/2 mutation is associated with seizure as an initial symptom in low-grade glioma:Areport of 311 Chinese adult glioma patients[J].Epilepsy Res,2015,109:100-105.
[19]DANG L,WHITE D W,GROSS S,et al.Cancer-associated IDH1mutations produce 2-hydroxyglutarate[J].Nature,2009,462(7274):739-744.
[20]KOLKER S,PAWLAK V,AHLEMEYER B,et al.NMDA receptor activation and respiratory chain complex V inhibition contribute to neurodegeneration in d-2-hydroxyglutaric aciduria[J].Eur J Neurosci,2002,16(1):21-28.
[21]杨卓,王新军,单峤,等.胶质瘤相关性癫痫患者术后痫性再发的临床特征及影响因素[J].医学研究生学报,2017,30(4):405-408.2018-11-23