IDH1突变在胶质瘤中的研究进展
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摘要
脑胶质瘤是一种常见的颅内原发恶性肿瘤,起源于神经胶质细胞,严重影响人类的健康。随着神经肿瘤分子的发展,异柠檬酸脱氢酶-1(isocitrate dehydrogenase,IDH1)已经成为目前胶质瘤分子标志物的研究热点。IDH1的突变引起2-羟基戊二酸(2-hydroxyglutaric acid,2-HG)异常增高,进一步导致DNA和组蛋白高甲基化,目前已经成为研究的潜在靶点,这一发现能够使胶质瘤的临床治疗获益。本文概述了突变型IDH1的功能,以及目前IDH1突变在胶质瘤发生机制中的作用。此外,还讨论了IDH1突变的胶质瘤的靶向治疗、免疫治疗及临床预后。
Brain glioma is a common primary intracranial malignant tumor,which originates from nerve glial cells and seriously affects human health.With the development of neurotumor molecules,isocitrate dehydrogenase(IDH1) has become a hot spot in the study of molecular markers of glioma.IDH1 mutation causes abnormal increase of 2-hydroxyglutaric acid(2-HG),further leading to DNA and histone hypermethylation,which has become a potential target for research,and this discovery can benefit the clinical treatment of glioma.This paper provides an overview of the function of mutant IDH1,and the role of IDH1 mutations in gliomagenesis.In addition,the targeted treatment,immunotherapy and clinical prognosis of IDH1 mutant glioma have been discussed.
Brain glioma is a common primary intracranial malignant tumor,which originates from nerve glial cells and seriously affects human health.With the development of neurotumor molecules,isocitrate dehydrogenase(IDH1) has become a hot spot in the study of molecular markers of glioma.IDH1 mutation causes abnormal increase of 2-hydroxyglutaric acid(2-HG),further leading to DNA and histone hypermethylation,which has become a potential target for research,and this discovery can benefit the clinical treatment of glioma.This paper provides an overview of the function of mutant IDH1,and the role of IDH1 mutations in gliomagenesis.In addition,the targeted treatment,immunotherapy and clinical prognosis of IDH1 mutant glioma have been discussed.
引文
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[4] Yan H,Parsons DW,Jin G,et al.IDH1 and IDH2 mutations in gliomas[J].N Engl J Med,2009,360:765-773.
[5] Leonardi R, Subramanian C, Jackowski S, et al. Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation[J].J Biol Chem,2012,287:14615-14620.
[6] Bleeker FE,Atai NA,Lamba S,et al.The prognostic IDH1R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma[J].Acta Neuropathol,2010,119:487-494.
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[11] Gross S,Cairns RA,Minden MD,et al.Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations[J].J Exp Med,2010,207:339-344.
[12] Shigeo Ohba,Yuichi Hirose.Biological significance of mutant isocitrate dehydrogenase 1 and 2 in gliomagenesis[J].Neurol Med Chir (Tokyo),2016,56(4): 170-179.
[13] Yang Z,Jiang B,Wang Y,et al.2-HG inhibits necroptosis by stimulating DNMT1-dependent hypermethylation of the RIP3 promoter[J].Cell Rep,2017,19(9):1846-1857.
[14] Matthew S Waitkus,Bill H Diplas,Hai Yan.Isocitrate dehydrogenase mutations in gliomas[J].Neuro Oncol,2016,18(1):16-26.
[15] Chowdhury R,Yeoh KK,Tian YM,et al.The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases[J].EMBO Rep,2011,12(5):463-469.
[16] Dimitrov L,Hong CS,Yang C,et al.New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma[J].Int J Med Sci,2015,12:201-213.
[17] Zhang C,Moore LM,Li X,et al.IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma[J].Neuro-oncology,2013,15:1114-1126.
[18] Koivunen P,Lee S,Duncan CG,et al.Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation[J].Nature,2012,483:484-488.
[19] Han CH,Batchelor TT.Isocitrate dehydrogenase mutation as a therapeutic target in gliomas[J].Chin Clin Oncol,2017,6(3):33.
[20] Rohle D,Popovici-Muller J,Palaskas N,et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells[J].Science,2013,340(6132):626-630.
[21] Peng Haiqin,Fu Jun,Li Zhanzhan,et al.The role of IDH1 gene mutation in gliomas and related targeted therapies[J].E-J Transl Med,2018,5(07):23-26.[彭海芹,付军,李战战,等.IDH1基因突变在胶质瘤中的作用机制及其靶向治疗研究[J].转化医学电子杂志,2018,5(07):23-26.]
[22] Turcan S, Fabius AW, Borodovsky A,et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine[J].Oncotarget,2013,4(10):1729-1736.
[23] Borodovsky A,Salmasi V,Turcan S,et al.5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft[J].Oncotarget,2013,4(10):1737-1747.
[24] Schumacher T,Bunse L,Pusch S,et al.A vaccine targeting mutant IDH1 induces antitumour immunity[J].Nature,2014,512:324-327.
[25] Pellegatta S,Valletta L,Corbetta C,et al.Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma[J].Acta Neuropathol Commun,2015,3:4.
[26] Yu Jialong,Huang Nanqu,Shi Shangpeng,et al.Research progress of isocitrate dehydrogenase 1/2 mutations and its inhibitor in gliomas[J].Journal of Clinical and Pathological Research,2018,38(5):1071-1076. [于佳龙, 黄南渠, 施尚鹏,等.异柠檬酸脱氢酶1/2突变及其抑制剂在脑胶质瘤中的研究进展[J].临床与病理杂志,2018,38(5):1071-1076.]
[27] Cairncross JG,Wang M,Jenkins RB,et al.Benefit from procarbazine,lomustine,and vincristine in oligodendroglial tumors is associated with mutation of IDH[J].J Clin Oncol,2014,32:783-790.
[28] van den Bent MJ,Brandes AA,Taphoorn MJ,et al.Adjuvant procarbazine,lomustine,and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma:Long-term follow-up of EORTC brain tumor group study 26951[J].J Clin Oncol,2013,31:344-350.
[29] Buckner J,Shaw E,Pugh S,et al.ATCT-09IDH1 R132H mutations in NRG oncology/RTOG 9802:Phase III study of radiation therapy (RT) alone vs RT plus procarbazine,CCNU,and vincristine (PCV) in patients with low grade glioma (LGG)[J].Neuro Oncol,2015,17(suppl 5):v3-v3.
[30] SongTao Q,Lei Y,Si G,et al.IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma[J].Cancer Sci,2012,103:269-273.
[31] Houillier C,Wang X,Kaloshi G,et al.IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas[J].Neurology,2010,75:1560-1566.
[32] Turkalp Z,Karamchandani J,Das S.IDH mutation in glioma:New insights and promises for the future[J].JAMA Neurol,2014,71(10):1319-1325.
[33] Sabha N,Knobbe CB,Maganti M,et al.Analysis of IDH mutation,1p/19q deletion,and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas[J].Neuro Oncol,2014,16(7):914-923.
[34] Louis DN,Perry A,Reifenberger G,et al.The 2016 World Health Organization classification of tumors of the central nervous system:A summary[J].Acta Neuropathol,2016,131(6):803-820.
[35] Wang F,Travins J,DeLaBarre B,et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation[J].Science,2013,340(6132):622-626.
[36] Losman JA,Looper RE,Koivune P,et al.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible[J].Science,2013,339(6127):1621-1625.
[37] Kernytsky A,Wang F,Hansen E,et al.IDH2 mutation induced histone and DNA hypermethylation is progressively reversed by small molecule inhibition[J].Blood,2014,125(2):296-304.
[2] Editing Group of Chinese Central Nervous System Glioma Diagnosis and Treatment Guidelines.Guidelines for the diagnosis and treatment of central nervous system gliomas in China[J].Chinese Medical Journal,2016,96(07):485-509.[《中国中枢神经系统胶质瘤诊断和治疗指南》编写组.中国中枢神经系统胶质瘤诊断和治疗指南[J].中华医学杂志,2016,96(07):485-509.]
[3] Parsons DW,Jones S,Zhang X,et al.An integrated genomic analysis of human glioblastoma multiforme[J].Science,2008,321(5897):1807-1812.
[4] Yan H,Parsons DW,Jin G,et al.IDH1 and IDH2 mutations in gliomas[J].N Engl J Med,2009,360:765-773.
[5] Leonardi R, Subramanian C, Jackowski S, et al. Cancer-associated isocitrate dehydrogenase mutations inactivate NADPH-dependent reductive carboxylation[J].J Biol Chem,2012,287:14615-14620.
[6] Bleeker FE,Atai NA,Lamba S,et al.The prognostic IDH1R132 mutation is associated with reduced NADP+-dependent IDH activity in glioblastoma[J].Acta Neuropathol,2010,119:487-494.
[7] Ichimura K,Narita Y,Hawkins CE.Diffusely infiltrating astrocytomas:Pathology,molecular mechanisms and markers[J].Acta Neuropathol,2015,129:789-808.
[8] Kloosterhof NK,Bralten LB,Dubbink HJ,et al.Isocitrate dehydrogenase-1 mutations:A fundamentally new understanding of diffuse glioma[J].Lancet Oncol,2011,12(1):83-91.
[9] Zhao S,Lin Y,Xu W,et al.Glioma-derived mutations in IDH1 dominantly inhibit IDH1 catalytic activity and induce HIF-1alpha[J].Science,2009,324:261-265.
[10] Dang L,White DW,Gross S,et al.Cancer-associated IDH1 mutations produce 2-hydroxyglutarate[J].Nature,2009,462:739-744.
[11] Gross S,Cairns RA,Minden MD,et al.Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations[J].J Exp Med,2010,207:339-344.
[12] Shigeo Ohba,Yuichi Hirose.Biological significance of mutant isocitrate dehydrogenase 1 and 2 in gliomagenesis[J].Neurol Med Chir (Tokyo),2016,56(4): 170-179.
[13] Yang Z,Jiang B,Wang Y,et al.2-HG inhibits necroptosis by stimulating DNMT1-dependent hypermethylation of the RIP3 promoter[J].Cell Rep,2017,19(9):1846-1857.
[14] Matthew S Waitkus,Bill H Diplas,Hai Yan.Isocitrate dehydrogenase mutations in gliomas[J].Neuro Oncol,2016,18(1):16-26.
[15] Chowdhury R,Yeoh KK,Tian YM,et al.The oncometabolite 2-hydroxyglutarate inhibits histone lysine demethylases[J].EMBO Rep,2011,12(5):463-469.
[16] Dimitrov L,Hong CS,Yang C,et al.New developments in the pathogenesis and therapeutic targeting of the IDH1 mutation in glioma[J].Int J Med Sci,2015,12:201-213.
[17] Zhang C,Moore LM,Li X,et al.IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma[J].Neuro-oncology,2013,15:1114-1126.
[18] Koivunen P,Lee S,Duncan CG,et al.Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation[J].Nature,2012,483:484-488.
[19] Han CH,Batchelor TT.Isocitrate dehydrogenase mutation as a therapeutic target in gliomas[J].Chin Clin Oncol,2017,6(3):33.
[20] Rohle D,Popovici-Muller J,Palaskas N,et al.An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells[J].Science,2013,340(6132):626-630.
[21] Peng Haiqin,Fu Jun,Li Zhanzhan,et al.The role of IDH1 gene mutation in gliomas and related targeted therapies[J].E-J Transl Med,2018,5(07):23-26.[彭海芹,付军,李战战,等.IDH1基因突变在胶质瘤中的作用机制及其靶向治疗研究[J].转化医学电子杂志,2018,5(07):23-26.]
[22] Turcan S, Fabius AW, Borodovsky A,et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine[J].Oncotarget,2013,4(10):1729-1736.
[23] Borodovsky A,Salmasi V,Turcan S,et al.5-azacytidine reduces methylation, promotes differentiation and induces tumor regression in a patient-derived IDH1 mutant glioma xenograft[J].Oncotarget,2013,4(10):1737-1747.
[24] Schumacher T,Bunse L,Pusch S,et al.A vaccine targeting mutant IDH1 induces antitumour immunity[J].Nature,2014,512:324-327.
[25] Pellegatta S,Valletta L,Corbetta C,et al.Effective immuno-targeting of the IDH1 mutation R132H in a murine model of intracranial glioma[J].Acta Neuropathol Commun,2015,3:4.
[26] Yu Jialong,Huang Nanqu,Shi Shangpeng,et al.Research progress of isocitrate dehydrogenase 1/2 mutations and its inhibitor in gliomas[J].Journal of Clinical and Pathological Research,2018,38(5):1071-1076. [于佳龙, 黄南渠, 施尚鹏,等.异柠檬酸脱氢酶1/2突变及其抑制剂在脑胶质瘤中的研究进展[J].临床与病理杂志,2018,38(5):1071-1076.]
[27] Cairncross JG,Wang M,Jenkins RB,et al.Benefit from procarbazine,lomustine,and vincristine in oligodendroglial tumors is associated with mutation of IDH[J].J Clin Oncol,2014,32:783-790.
[28] van den Bent MJ,Brandes AA,Taphoorn MJ,et al.Adjuvant procarbazine,lomustine,and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma:Long-term follow-up of EORTC brain tumor group study 26951[J].J Clin Oncol,2013,31:344-350.
[29] Buckner J,Shaw E,Pugh S,et al.ATCT-09IDH1 R132H mutations in NRG oncology/RTOG 9802:Phase III study of radiation therapy (RT) alone vs RT plus procarbazine,CCNU,and vincristine (PCV) in patients with low grade glioma (LGG)[J].Neuro Oncol,2015,17(suppl 5):v3-v3.
[30] SongTao Q,Lei Y,Si G,et al.IDH mutations predict longer survival and response to temozolomide in secondary glioblastoma[J].Cancer Sci,2012,103:269-273.
[31] Houillier C,Wang X,Kaloshi G,et al.IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas[J].Neurology,2010,75:1560-1566.
[32] Turkalp Z,Karamchandani J,Das S.IDH mutation in glioma:New insights and promises for the future[J].JAMA Neurol,2014,71(10):1319-1325.
[33] Sabha N,Knobbe CB,Maganti M,et al.Analysis of IDH mutation,1p/19q deletion,and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas[J].Neuro Oncol,2014,16(7):914-923.
[34] Louis DN,Perry A,Reifenberger G,et al.The 2016 World Health Organization classification of tumors of the central nervous system:A summary[J].Acta Neuropathol,2016,131(6):803-820.
[35] Wang F,Travins J,DeLaBarre B,et al.Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation[J].Science,2013,340(6132):622-626.
[36] Losman JA,Looper RE,Koivune P,et al.(R)-2-hydroxyglutarate is sufficient to promote leukemogenesis and its effects are reversible[J].Science,2013,339(6127):1621-1625.
[37] Kernytsky A,Wang F,Hansen E,et al.IDH2 mutation induced histone and DNA hypermethylation is progressively reversed by small molecule inhibition[J].Blood,2014,125(2):296-304.