en
×

分享给微信好友或者朋友圈

使用微信“扫一扫”功能。
通讯作者:

季晶,E-mail:jijing@njmu.edu.cn

中图分类号:R739.41

文献标识码:A

文章编号:1007-4368(2023)02-283-08

DOI:10.7655/NYDXBNS20230220

参考文献 1
WELLER M,WICK W,ALDAPE K,et al.Glioma[J].Nat Rev Dis Primers,2015,1:15017
参考文献 2
LAPOINTE S,PERRY A,BUTOWSKI N A.Primary brain tumours in adults[J].Lancet,2018,392(10145):432-446
参考文献 3
OSTROM Q T,DE BLANK P M,KRUCHKO C,et al.Al⁃ ex’s lemonade stand foundation infant and childhood pri⁃ mary brain and central nervous system tumors diagnosed in the United States in 2007 ⁃ 2011[J].Neuro Oncol,2015,16(Suppl 10):x1-x36
参考文献 4
LOUIS D N,PERRY A,WESSELING P,et al.The 2021 WHO classification of tumors of the central nervous sys⁃ tem:a summary[J].Neuro Oncol,2021,23(8):1231-1251
参考文献 5
ALDERA A P,GOVENDER D.Gene of the month:H3F3A and H3F3B[J].J Clin Pathol,2022,75(1):1-4
参考文献 6
RAY⁃GALLET D,ALMOUZNI G.The histone H3 family and its deposition pathways[M]//FANG D,HAN J.His⁃ tone mutations and cancer.Singapore;Springer Singa⁃ pore,2021:17-42
参考文献 7
KUMAR V C,PAI R.Genes of the month:H3.3 histone genes:H3F3A and H3F3B[J].J Clin Pathol,2021,74(12):753-758
参考文献 8
TROVATO M,PATIL V,GEHRE M,et al.Histone vari⁃ ant H3.3 mutations in defining the chromatin function in mammals[J].Cells,2020,9(12):2716
参考文献 9
MILLÁN ⁃ ZAMBRANO G,BURTON A,BANNISTER A J,et al.Histone post ⁃translational modifications ⁃ cause and consequence of genome function[J].Nat Rev Genet,2022,23(9):563-580
参考文献 10
SHI L,WEN H,SHI X.The histone variant H3.3 in tran⁃ scriptional regulation and human disease[J].J Mol Biol,2017,429(13):1934-1945
参考文献 11
TAGAMI H,RAY⁃GALLET D,ALMOUZNI G,et al.His⁃ tone H3.1 and H3.3 complexes mediate nucleosome as⁃ sembly pathways dependent or independent of DNA syn⁃ thesis[J].Cell,2004,116(1):51-61
参考文献 12
XIONG C,WEN Z,YU J,et al.UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis ⁃regulatory elements of genes in mouse ES cells[J].BMC Biol,2018,16(1):110
参考文献 13
HUANG X,LIU J,MA Q.Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines[J].FEBS Open Bio,2020,10(10):2182-2190
参考文献 14
VALENZUELA M,AMATO R,SGURA A,et al.The mul⁃ tiple facets of ATRX protein[J].Cancers,2021,13(9):2211
参考文献 15
MAHMUD I,LIAO D.DAXX in cancer:phenomena,pro⁃ cesses,mechanisms and regulation[J].Nucleic Acids Res,2019,47(15):7734-7752
参考文献 16
UDUGAMA M,HII L,GARVIE A,et al.Mutations inhib⁃ iting KDM4B drive ALT activation in ATRX⁃mutated glio⁃ blastomas[J].Nat Commun,2021,12(1):2584
参考文献 17
SCHWARTZENTRUBER J,KORSHUNOV A,LIU X Y,et al.Driver mutations in histone H3.3 and chromatin re⁃ modelling genes in paediatric glioblastoma[J].Nature,2012,482(7384):226-231
参考文献 18
LOUIS D N,WESSELING P,ALDAPE K,et al.cIMPACT⁃ NOW update 6:new entity and diagnostic principle rec⁃ ommendations of the cIMPACT⁃Utrecht meeting on future CNS tumor classification and grading[J].Brain Pathol,2020,30(4):844-856
参考文献 19
LOWE B R,MAXHAM L A,HAMEY J J,et al.Histone H3 mutations:an updated view of their role in chromatin deregulation and cancer[J].Cancers,2019,11(5):660
参考文献 20
WU G,BRONISCER A,MCEACHRON T A,et al.Somat⁃ ic histone H3 alterations in pediatric diffuse intrinsic pon⁃ tine gliomas and non ⁃ brainstem glioblastomas[J].Nat Genet,2012,44(3):251-253
参考文献 21
STURM D,WITT H,HOVESTADT V,et al.Hotspot mu⁃ tations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma[J].Cancer Cell,2012,22(4):425-437
参考文献 22
KAY M D,PARIURY H E,PERRY A,et al.Extracranial metastases from glioblastoma with primitive neuronal com⁃ ponents on FDG PET/CT[J].Clin Nucl Med,2020,45(3):e162-e164
参考文献 23
MOHIUDDIN S,MARAKA S,USMAN BAIG M,et al.Case series of diffuse extraneural metastasis in H3F3A mutant high⁃grade gliomas:clinical,molecular phenotype and literature review[J].J Clin Neurosci,2021,89:405-411
参考文献 24
KORSHUNOV A,RYZHOVA M,HOVESTADT V,et al.Integrated analysis of pediatric glioblastoma reveals a sub⁃ set of biologically favorable tumors with associated molec⁃ ular prognostic markers[J].Acta Neuropathol,2015,129(5):669-678
参考文献 25
NEUMANN J E,DOROSTKAR M M,KORSHUNOV A,et al.Distinct histomorphology in molecular subgroups of glioblastomas in young patients[J].J Neuropathol Exp Neurol,2016,75(5):408-414
参考文献 26
ROUX A,PALLUD J,SAFFROY R,et al.High⁃grade gli⁃ omas in adolescents and young adults highlight histomo⁃ lecular differences from their adult and pediatric counter⁃ parts[J].Neuro Oncol,2020,22(8):1190-1202
参考文献 27
LIM K Y,WON J K,PARK C K,et al.H3 G34⁃mutant high⁃grade glioma[J].Brain Tumor Pathol,2021,38(1):4-13
参考文献 28
YOSHIMOTO K,HATAE R,SANGATSUDA Y,et al.Prevalence and clinicopathological features of H3.3 G34⁃ mutant high ⁃ grade gliomas:a retrospective study of 411 consecutive glioma cases in a single institution[J].Brain Tumor Pathol,2017,34(3):103-112
参考文献 29
王玮,王雷明,卢德宏,等.伴有H3 G34R突变的高级别胶质瘤临床病理学观察[J].中华病理学杂志,2020,49(12):1267-1271
参考文献 30
KHAZAEI S,DE JAY N,DESHMUKH S,et al.H3.3 G34W promotes growth and impedes differentiation of os⁃ teoblast⁃like mesenchymal progenitors in giant cell tumor of bone[J].Cancer Discov,2020,10(12):1968-1987
参考文献 31
COLEMAN C,STOLLER S,GROTZER M,et al.Pediat⁃ ric hemispheric high ⁃ grade glioma:targeting the future [J].Cancer Metastasis Rev,2020,39(1):245-260
参考文献 32
STOCCO C,PILOTTO C,PASSONE E,et al.Presentation and symptom interval in children with central nervous sys⁃ tem tumors.a single ⁃ center experience[J].Childs Nerv Syst,2017,33(12):2109-2116
参考文献 33
SMITS M.MRI biomarkers in neuro⁃oncology[J].Nat Rev Neurol,2021,17(8):486-500
参考文献 34
PUNTONET J,DANGOULOFF⁃ROS V,SAFFROY R,et al.Historadiological correlations in high ⁃ grade glioma with the histone 3.3 G34R mutation[J].J Neuroradiol,2018,45(5):316-322
参考文献 35
ONISHI S,AMATYA V J,KARLOWEE V,et al.Radio⁃ logical and immunostaining characteristics of H3.3 G34R⁃ mutant glioma:a report of 3 cases and review of the litera⁃ ture[J].Pediatr Neurosurg,2020,55(5):319-325
参考文献 36
KUROKAWA R,BABA A,KUROKAWA M,et al.Neuro⁃ imaging features of diffuse hemispheric glioma,H3 G34⁃ mutant:a case series and systematic review[J].J Neuro⁃ imaging,2021,32(1):17-27
参考文献 37
唐文天,张梓枫,尹建新,等.常规MRI特征在弥漫性星形细胞瘤IDH基因突变预测中的临床价值[J].南京医科大学学报(自然科学版),2022,42(3):376-381
参考文献 38
OVERCAST W B,DAVIS K M,HO C Y,et al.Advanced imaging techniques for neuro ⁃oncologic tumor diagnosis,with an emphasis on PET ⁃ MRI imaging of malignant brain tumors[J].Curr Oncol Rep,2021,23(3):34
参考文献 39
VETTERMANN F J,FELSBERG J,REIFENBERGER G,et al.Characterization of diffuse gliomas with histone H3⁃ G34 mutation by MRI and dynamic 18F⁃FET PET[J].Clin Nucl Med,2018,43(12):895-898
参考文献 40
MARNER L,LUNDEMANN M,SEHESTED A,et al.Di⁃ agnostic accuracy and clinical impact of 18FFET PET in childhood CNS tumors[J].Neuro Oncol,2021,23(12):2107-2116
参考文献 41
龚俊杰,刘秀秀,王平,等.代谢组学在胶质母细胞瘤相关研究中的应用[J].南京医科大学学报(自然科学版),2021,41(2):296-305
参考文献 42
MAYERHOEFER M E,MATERKA A,LANGS G,et al.Introduction to radiomics[J].J Nucl Med,2020,61(4):488-495
参考文献 43
ZHAO J,HUANG Y,SONG Y,et al.Diagnostic accuracy and potential covariates for machine learning to identify IDH mutations in glioma patients:evidence from a meta ⁃ analysis[J].Eur Radiol,2020,30(8):4664-4674
参考文献 44
GUO W,SHE D,XING Z,et al.Multiparametric MRI ⁃ based radiomics model for predicting H3 K27M mutant status in diffuse midline glioma:a comparative study across different sequences and machine learning tech⁃ niques[J].Front Oncol,2022,12:796583
参考文献 45
HOHM A,KARREMANN M,GIELEN G H,et al.Mag⁃ netic resonance imaging characteristics of molecular sub⁃ groups in pediatric H3 K27M mutant diffuse midline glio⁃ ma[J].Clin Neuroradiol,2022,32(1):249-258
参考文献 46
LASOCKI A,ANJARI M,ÖRS KOKURCAN S,et al.Con⁃ ventional MRI features of adult diffuse glioma molecular subtypes:a systematic review[J].Neuroradiology,2021,63(3):353-362
参考文献 47
GONÇALVES F G,VIAENE A N,VOSSOUGH A.Ad⁃ vanced magnetic resonance imaging in pediatric glioblas⁃ tomas[J].Front Neurol,2021,12:733323
参考文献 48
BARRAGáN ⁃PéREZ E J,ALTAMIRANO ⁃VERGARA C E,ALVAREZ ⁃AMADO D E,et al.The role of time as a prognostic factor in pediatric brain tumors:a multivariate survival analysis[J].Pathol Oncol Res,2020,26(4):2693-2701
参考文献 49
PICART T,BARRITAULT M,PONCET D,et al.Charac⁃ teristics of diffuse hemispheric gliomas,H3 G34 ⁃ mutant in adults[J].Neurooncol Adv,2021,3(1):vdab061
参考文献 50
HODGSON J M,DOUCH C,HARTLEY L,et al.Problem solving in clinical practice:an unusual cause of multifo⁃ cal brain lesions[J].Arch Dis Child Educ Pract Ed,2021,106(5):299-303
参考文献 51
HUANG T Y,PIUNTI A,LULLA R R,et al.Detection of histone H3 mutations in cerebrospinal fluid ⁃ derived tu⁃ mor DNA from children with diffuse midline glioma[J].Acta Neuropathol Commun,2017,5(1):28
参考文献 52
GESSI M,GIELEN G H,HAMMES J,et al.H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system(CNS⁃PNET)and pediatric glio⁃ blastomas:possible diagnostic and therapeutic implica⁃ tions?[J].J Neurooncol,2013,112(1):67-72
参考文献 53
WANG L,SHAO L,LI H,et al.Histone H3.3 G34⁃mutant diffuse gliomas in adults[J].Am J Surg Pathol,2022,46(2):249-257
参考文献 54
GILANI A,KLEINSCHMIDT⁃DEMASTERS B K.Morpho⁃ logical diversity in H3G34 ⁃ mutant high ⁃ grade gliomas:ganglionic and epithelioid features[J].Clin Neuropathol,2021,40(1):4-10
参考文献 55
MORRIS M,DRISCOLL M,HENSON J W,et al.Low ⁃ grade gemistocytic morphology in H3 G34R ⁃Mutant glio⁃ mas and concurrent K27M mutation:clinicopathologic findings[J].J Neuropathol Exp Neurol,2020,79(10):1038-1043
参考文献 56
SASAKI S,TOMOMASA R,NOBUSAWA S,et al.Ana⁃ plastic pleomorphic xanthoastrocytoma associated with an H3G34 mutation:a case report with review of literature [J].Brain Tumor Pathol,2019,36(4):169-173
参考文献 57
ANDREIUOLO F,LISNER T,ZLOCHA J,et al.H3F3A⁃ G34R mutant high grade neuroepithelial neoplasms with glial and dysplastic ganglion cell components[J].Acta Neuropathol Commun,2019,7(1):78
参考文献 58
KORSHUNOV A,CAPPER D,REUSS D,et al.Histologi⁃ cally distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single no⁃ sologic entity[J].Acta neuropathol,2016,131(1):137-146
参考文献 59
邹婉婧,崔云,何艳姣,等.H3 G34突变型弥漫性半球胶质瘤临床和病理学特征分析[J].中华神经外科杂志,2021,37(11):1090-1096
参考文献 60
MACKAY A,BURFORD A,CARVALHO D,et al.Inte⁃ grated molecular meta ⁃analysis of 1,000 pediatric high ⁃ grade and diffuse intrinsic pontine glioma[J].Cancer Cell,2017,32(4):520-537
参考文献 61
WANG Y,XIE X,LI S,et al.Co⁃overexpression of RIOK1 and AKT1 as a prognostic risk factor in glioma[J].J Can⁃ cer,2021,12(19):5745-5752
参考文献 62
DAVIS R J,WELCKER M,CLURMAN B E.Tumor sup⁃ pression by the Fbw7 ubiquitin ligase:mechanisms and opportunities[J].Cancer Cell,2014,26(4):455-464
参考文献 63
HU W,DUAN H,ZHONG S,et al.High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma,H3 G34⁃mutant:a glimmer of hope?[J].J Transl Med,2022,20(1):64
参考文献 64
NABORS L B,PORTNOW J,AHLUWALIA M,et al.Cen⁃ tral nervous system cancers,version 3.2020,NCCN clini⁃ cal practice guidelines in oncology[J].J Nati Comp Canc Netw,2020,18(11):1537-1570
参考文献 65
SULMAN E P,ISMAILA N,ARMSTRONG T S,et al.Ra⁃ diation therapy for glioblastoma:american society of clini⁃ cal oncology clinical practice guideline endorsement of the American Society for radiation oncology guideline[J].J Clin Oncol,2017,35(3):361-369
参考文献 66
WELLER M,VAN DEN BENT M,PREUSSER M,et al.EANO guidelines on the diagnosis and treatment of dif⁃ fuse gliomas of adulthood[J].Nat Rev Clin Oncol,2021,18(3):170-186
参考文献 67
DONSON A M,ADDO ⁃YOBO S O,HANDLER M H,et al.MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glio⁃ blastoma[J].Pediatr Blood Cancer,2007,48(4):403-407
参考文献 68
WELLER J,TZARIDIS T,MACK F,et al.Health⁃related quality of life and neurocognitive functioning with lomus⁃ tine ⁃ temozolomide versus temozolomide in patients with newly diagnosed,MGMT ⁃ methylated glioblastoma(Ce⁃ TeG/NOA ⁃ 09):a randomised,multicentre,open ⁃ label,phase 3 trial[J].Lancet Oncol,2019,20(10):1444-1453
参考文献 69
LUCAS C G,MUELLER S,REDDY A,et al.Diffuse hemi⁃ spheric glioma,H3 G34⁃mutant:genomic landscape of a new tumor entity and prospects for targeted therapy[J].Neurooncol,2021,23(11):1974-1976
参考文献 70
SWEHA S R,CHUNG C,NATARAJAN S K,et al.Epige⁃ netically defined therapeutic targeting in H3.3G34R/V high ⁃grade gliomas[J].Sci transl med,2021,13(615):eabf7860
参考文献 71
FRIEDMAN G K,JOHNSTON J M,BAG A K,et al.On⁃ colytic HSV⁃1 G207 immunovirotherapy for pediatric high ⁃grade gliomas[J].N Engl J Med,2021,384(17):1613-1622
参考文献 72
MACKAY A,BURFORD A,MOLINARI V,et al.Molecu⁃ lar,pathological,radiological,and immune profiling of non⁃ brainstem pediatric high ⁃ grade glioma from the HERBY phase Ⅱ randomized trial[J].Cancer Cell,2018,33(5):829-842
参考文献 73
VUONG H G,LE H T,DUNN I F.The prognostic signifi⁃ cance of further genotyping H3G34 diffuse hemispheric gliomas[J].Cancer,2022,128(10):1907-1912
参考文献 74
TINKLE C L,BRONISCER A,CHIANG J,et al.Phase I study using crenolanib to target PDGFR kinase in chil⁃ dren and young adults with newly diagnosed DIPG or re⁃ current high⁃grade glioma,including DIPG[J].Neuroon⁃ col Adv,2021,3(1):vdab179
目录contents

    摘要

    H3 G34突变的弥漫性半球胶质瘤是2021年WHO新定义的高级别胶质瘤,其标志性特征是H3F3A基因突变,导致组蛋白H3.3第34位甘氨酸转变为精氨酸或缬氨酸。这一亚型好发于儿童及青少年,临床较为少见,发病机制仍未明确。影像学表现不典型,早期容易误诊漏诊,确诊有赖于免疫组化和分子病理。治疗以手术为主,辅以术后放化疗,但预后往往不佳。文章综述了该亚型的相关研究进展,以期提高临床医师对该疾病的认识。

    Abstract

    Diffuse hemispheric glioma,H3 G34-mutant is a high -grade glioma,which is newly defined by WHO in 2021,and its hallmark is the H3F3A gene mutation by exchanging glycine at position 34 of histone H3.3 for arginine or valine. This subtype occurs primarily in children and young adults and is clinically rare,of which the pathogenesis remains unclear. Imaging manifestations are not typical,and it is easy to be misdiagnosed and missed in the early stage. The diagnosis depends on immunohistochemistry and molecular pathology. Surgery is essential when it comes to treatment,supplemented by the postoperative radiotherapy and chemotherapy. Unfortunately,the prognosis remains poor. Here we reviewed the related research progress of this subtype in order to improve clinicians’understanding of the disease.

  • 胶质瘤是指由神经胶质细胞或其前体细胞癌变所产生的肿瘤,是一组各具异质性的神经肿瘤的统称[1]。根据其生长方式以及有无异柠檬酸脱氢酶 (isocitrate dehydrogenase,IDH)基因突变,可分为弥漫性胶质瘤与非弥漫性/局限性胶质瘤两大类[2]。非弥漫性胶质瘤是指相对良性的、单纯手术治疗即可治愈的胶质瘤,如 WHO Ⅰ级的毛细胞星形胶质瘤。弥漫性胶质瘤则表现出更高的侵袭性,往往需要术后联合放化疗。其根据生长方式与恶性程度的不同,传统上又可分为WHO Ⅱ级、Ⅲ级与Ⅳ级, Ⅲ级与Ⅳ级合称为高级别胶质瘤(high grade glio⁃ ma,HGG)。对0~14岁儿童来说,尽管HGG仅占所有中枢神经系统(central nervous system,CNS)肿瘤的11.1%,但其预后较差,5年生存率只有28.4%[3]。主要发生于儿童群体的胶质瘤与成人胶质瘤在生物学上有许多不同,但是在过去,儿童胶质瘤的分类分级与成人胶质瘤基本一致,都采用组织学分型。随着相关研究的深入,儿童胶质瘤分型也开始采用组织学与分子生物学相结合的标准。在 2021 年的WHO CNS肿瘤分类中[4],儿童胶质瘤分类有了较大的改动,取消了胶质母细胞瘤(glioblastoma, GBM)这一概念,取而代之的是儿童 HGG,包括 H3 G34 突变型弥漫性半球胶质瘤(diffuse hemispheric glioma,H3 G34⁃mutant,H3 G34 DHG)、H3 K27突变型弥漫性中线胶质瘤、H3与IDH野生型胶质瘤、婴儿型半球胶质瘤 4 种。其中,首次加入了 H3 G34 DHG这一新的亚型,该型胶质瘤在过去几年中得到了学界的广泛关注。本文总结了H3 G34 DHG的临床特征与诊疗进展,以期加深临床医师对该疾病的认识。

  • 1 组蛋白

  • 组蛋白是真核细胞染色质的重要组成部分,包括 5 种家族:H1/5、H2、H3、H4。组蛋白 H2A、H2B、 H3、H4 各两分子共同组成组蛋白八聚体,146~147 个碱基对的 DNA 缠绕其上形成核小体[5]。根据组蛋白与 DNA 的结合是否依赖于 DNA 复制,可将其分为经典组蛋白与非经典组蛋白,后者又称组蛋白变体。仅在细胞 S 期的 DNA 合成过程中产生并与之结合的组蛋白称为经典组蛋白,这一特性也被称为复制依赖性。而组蛋白变体则在整个细胞周期中表达,不存在 S 期的高表达峰[6]。其在相应的分子伴侣的协助下进入核小体,并替换经典组蛋白,影响染色质开放性,进而在细胞增殖、分化等生物学过程中发挥重要作用。H3.3即为组蛋白H3家族的一个重要变体,由2条单基因H3F3A、H3F3B独立编码,在调控基因表达和染色质构象中发挥着复杂的作用[7]。研究表明H3.3在基因组中分布不均,在转录基因、调控元件、端粒与着丝粒周围多出现富集[8]。同时,考虑到组蛋白本身常携带大量的翻译后修饰(post⁃translational modification,PTM)[9],提示这一变体可能还有许多潜在的生物学功能有待发现。

  • 目前已确定组蛋白H3.3有两种特异性分子伴侣与之结合:组蛋白细胞周期调节剂A(histone cell cy⁃ cle regulator A,HIRA)复合物和死亡结构域相关蛋白 (death domain⁃associated protein,DAXX)/α⁃地中海贫血X连锁智力低下蛋白(α⁃thalassemia X⁃linked men⁃ tal retardation protein,ATRX)复合物[10]。HIRA 基因最早是在先天性遗传病DiGeorge综合征患者所缺失的染色体中鉴定出来的,研究人员认为其在染色质结构与组蛋白代谢中发挥重要作用,后来被证实为 H3.3的特异性伴侣[11]。HIRA与钙调磷酸酶结合蛋白1(calcineurin⁃binding protein 1,CABIN1)、泛核蛋白1/2(ubinuclein1/2,UBN1/2)共同组合成复合物后,介导H3.3沉积于顺式作用元件区域[12]。但是,CAB⁃ IN1和UBN1/2在这一过程中究竟发挥何种作用尚未完全明确。最近的研究显示,HIRA复合物与抗增殖蛋白(prohibitin,PHB)相互作用,促进H3.3沉积于间充质标志物启动子区域,进而促进了乳腺癌细胞的上皮间质转化(epithelial ⁃ to ⁃ mesenchymal transition, EMT)[13]。但HIRA是否参与胶质瘤发生尚不清楚。 DAXX是一种Fas结合蛋白,介导细胞凋亡,而ATRX 则是染色质重塑因子(switch/sucrose nonfermentable, SWI/SNF)家族中的一员,参与 DNA 修复与端粒维持[14-15]。DAXX/ATRX复合物负责将H3.3转运至端粒、中心周围区、逆转录病毒元件(endogenous retrovi⁃ ral elements,ERV)等异染色质区域[10]。Udugama 等[16] 的研究揭示了H3 G34R突变抑制了组蛋白去甲基化酶KDM4B,并与ATRX突变协同作用,共同促进 GBM 中的端粒替代延长(alternative lengthening of telomeres,ALT)。尽管已在儿童 GBM 中观察到了 DAXX/ATRX 突变[17],但 DAXX 如何参与 H3 G34 DHG进展仍有待进一步挖掘。

  • 2 概述

  • H3 G34 DHG的概念主要来源于其分子生物学定义。其位于染色体1q42.12的H3F3A基因第35位密码子发生杂合突变,导致组蛋白H3.3的第34位氨基酸由甘氨酸(glycine,G)转变为精氨酸(arginine,R) 或缬氨酸(valine,V)[18]。尽管H3F3B基因也可以独立编码H3.3,但目前仍不清楚为何这一突变全部发生于 H3F3A。此外,临床发现 G34R 突变远多于 G34V,这一现象背后的原因亦有待探索[19]。2012年,两个不同的研究组通过高通量测序分别独立发现了儿童GBM中的H3F3A突变[1720]。随后,Sturm等[21] 发现了G34突变的GBM亚群的低甲基化水平,由此首次将其划分为GBM的一个表观遗传学亚型。随着相关研究的不断深入,这一亚型最终在 2021 年 WHO CNS肿瘤分类中得到明确。H3 G34 DHG主要好发于儿童及青少年人群,且病变几乎全部位于一侧大脑半球[18],但近年来有颅外广泛转移的报道[22-23]。值得注意的是,H3 G34 DHG 的阳性率在地区间存在较大差异。西欧的数据显示,该病占所有 HGG 的 14%~16%[24-26],但日韩的研究发现,这一亚型在所有胶质瘤中仅占1%上下[27-28]。国内的王玮等[29] 在323 例HGG中检出5例,检出率为1.5%,考虑到日韩的数据中包含一部分低级别胶质瘤病例,这一检出率应是合理的,但东亚地区阳性率较低的原因仍有待研究。 H3F3A突变在骨巨细胞瘤中也被观察到,最近的研究发现G34W可维持成骨细胞样祖细胞的转化状态,以促进肿瘤生长[30]

  • H3 G34 DHG的临床表现较为多样,主要与病变累及的结构和肿瘤进展程度相关。对于半球肿瘤患者来说,常可能出现不同类型的癫痫和局灶性神经功能缺损,也可能表现为经典的颅内压增高症状如头痛、恶心呕吐和视乳头水肿[31]。但是,一方面CNS肿瘤发病率较低,另一方面这些症状往往不够典型,也常出现在其他更为常见且相对较轻的疾病中,如急性胃肠炎、偏头痛等,导致部分临床医师忽视了CNS肿瘤的鉴别诊断,造成误诊、漏诊。此外,颅内肿瘤还可能导致认知行为改变、情绪改变等[32]。对于年幼的患儿来说,这些表现有时不被重视,以致延误诊断。详尽的病史采集与细致的体格检查是所有诊断的基石,临床医师应提高对儿童和青少年人群肿瘤性疾病的警惕性。

  • 3 影像与诊断

  • 影像学检查是 CNS 肿瘤诊断和评估的重要工具,包括 CT、MRI 和正电子发射断层扫描(positron emission tomography,PET)。其中,MRI在胶质瘤的诊疗过程中具有无可置疑的核心地位[33]。但是,H3 G34 DHG 的 MR 表现复杂多变,缺乏典型特征[34]。 Onishi等[35] 的研究表明,该亚型一般表现为T1低⁃等信号、T2/液体衰减反转恢复序列(fluid attenuated in⁃ version recovery,FLAIR)高信号、弥散加权成像(diffu⁃ sion⁃weighted imaging,DWI)高信号的占位,伴轻度的瘤周水肿。Kurokawa等[36] 系统回顾验证了这一观点,同时观察到肿瘤常边界不清,造影后呈现不同程度的增强。22%的肿瘤可见钙化,42%的病例出现瘤内出血,49%的患者观察到肿瘤囊变/坏死。对于完善了灌注成像,如动脉自旋标记(arterial spin labeling, ASL)或者动态磁敏感对比成像(dynamic susceptibili⁃ ty contrast,DSC)的患者,50%~64%出现脑血流升高。磁共振波谱(magnetic resonance spectroscopy, MRS)对于颅内肿瘤的鉴别诊断具有一定的意义,约 58%的患者观察到升高的脂质/乳酸(lipid lactate,LL) 峰和增加的胆碱/N⁃乙酰天冬氨酸(choline/N⁃acetyl aspartate,Cho/NAA)比值[36]。尽管常规MRI特征在胶质瘤部分亚型(如IDH突变型)的诊断中显示出一定的效能[37],但H3 G34 DHG的MR表现具有明显的异质性,单纯依靠MRI作出诊断较为困难。PET主要依靠静脉注入的放射性示踪剂探测肿瘤环境,以提供代谢功能成像[38]。用于脑肿瘤的示踪剂主要包括18F⁃氟脱氧葡萄糖(18F⁃fluorodeoxyglucose,FDG)和氨基酸类如 18F ⁃氟乙基酪氨酸(18F ⁃fluoroethyltyrosine,FET)。 Vettermann 等[39] 运用 18F⁃FET PET 研究 8 例 H3 G34 DHG后发现,该亚型在最大肿瘤本底比(maximal tu⁃mor⁃to⁃background ratio,TBRmax)、生物肿瘤体积(bio⁃ logic tumor volume,BTV)和最小达峰时间(minimal time⁃to⁃peak,TTPmin)上具有相当的一致性,提示18F⁃ FET PET 结合MRI或许可以提高诊断准确性,至少在鉴别肿瘤与非肿瘤性疾病中发挥作用[40]。代谢失调是胶质瘤的一大重要特征[41],但代谢组学在 H3 G34 DHG中的研究仍有待深入。CT在诊断中价值有限,H3 G34 DHG常表现为高密度影[36]

  • 近年来,影像组学或称放射组学,作为新兴领域不断得到发展,其从影像中提取定量数据,与疾病特征等建立关联,以期解决诊断、疗效评估等临床问题[42],机器学习则常作为影像组学的一种研究工具。目前,影像组学已初步应用于预测胶质瘤的基因突变情况。Zhao等[43] 的Meta分析显示,机器学习在预测胶质瘤 IDH 突变方面展现了出色的诊断效能,其总的敏感性和特异性分别为 88%和 87%。此外,也已有数项研究聚焦于H3 K27M突变的弥漫性中线胶质瘤,并展示出了有希望的结果[44-45]。La⁃ socki等[46] 的系统评价表明,常规MR序列,包括T1、 T2、FLAIR、DWI和T1增强,在胶质瘤的分子分型诊断中仍然很有价值。但是可能是因为H3 G34 DHG 发病率较低的原因,目前尚没有影像组学与其相关的研究。随着机器学习和人工智能的不断发展,这两种技术或许在今后可以用于H3 G34 DHG的诊断与评估。此外,目前也缺乏一些MR新技术如弥散张量成像(diffusion tensor imaging,DTI)、扩散峰度成像(diffusion kurtosis imaging,DKI)、化学交换饱和转移(chemical exchange saturation transfer,CEST)成像和血氧水平依赖(blood⁃oxygen⁃level⁃dependent, BOLD)成像等在H3 G34 DHG中的应用[3847]

  • 对于脑肿瘤患儿来说,早期发现与早期治疗是影响患儿生存质量与预后的重要因素[48]。但 H3 G34 DHG因其缺乏特征性的影像学表现,往往给临床决策带来极大困难,需与感染性、免疫性、代谢性疾病以及其他肿瘤等相鉴别。但许多患者在早期被误诊为脑炎、多发性硬化、CNS淋巴瘤或动静脉畸形等[49]。除完善脑电图、头颅血管检查外,脑脊液检查也是十分必要的,应包括常规、生化、细菌培养,更应完善脑脊液细胞学、病原学、IgG、寡克隆带、抗体组套等检查。Hodgson等[50] 详细报道了1例初期误诊为获得性脱髓鞘综合征的患儿的诊治经过,其激素冲击治疗未见明显好转,该患儿最终通过组织活检明确诊断。随着技术进步,脑肿瘤液体活检的临床应用越发成为可能,Huang 等[51] 通过 Sanger测序和巢式 PCR 首次在患儿脑脊液中检测到 H3.3 G34V突变,但其诊断效能尚待进一步的探索。

  • 4 病理特征

  • H3 G34 DHG 的组织形态学具有明显的异质性,大部分镜下表现为GBM样,但有时也呈现为原始神经外胚层肿瘤(primitive neuroectodermal tumor, PNET)样[52],少数表现为间变性星形细胞瘤(ana⁃ plastic astrocytoma,AA)[53]。此外,表现为间变神经节胶质瘤(anaplastic ganglioglioma)[54]、低级别肥胖细胞型星形细胞瘤(gemistocytic astrocytoma)[55]、间变性多形性黄色星形细胞瘤(anaplastic pleomorphic xanthoastrocytoma)[56],以及含发育不良的神经节成分的神经上皮肿瘤(neuroepithelial neoplasms with dysplastic ganglion cell components)[57] 的病例也见诸报道。目前仍不清楚为何H3 G34 DHG这一亚型可拥有如此广泛的形态学谱。

  • H3 G34 DHG的确诊主要依赖于免疫组化和分子病理,其一般性的免疫组化表现包括:胶质纤维酸性蛋白(glial fibrillary acidic protein,GFAP)阳性、 P53 阳性、突触素(synaptophysin,Syn)阳性、少突胶质细胞转录因子 2(oligodendrocyte transcription fac⁃ tor 2,Olig2)阴性与 ATRX 阴性[295358-59]。除 H3F3A 突变外,典型的基因特征还包括:P53突变,O⁃6⁃甲基鸟嘌呤⁃DNA 甲基转移酶(O ⁃ 6 ⁃ methylguanine ⁃ DNA methyltransferase,MGMT)启动子甲基化,IDH、 BRAF V600E 与端粒酶逆转录酶(telomerase reverse transcriptase,TERT)启动子野生型[274953]。随着研究深入,其他相伴随的基因突变也渐渐被发现。Kors⁃ hunov 等[58] 检测到了一系列癌基因改变,包括血小板衍生生长因子受体α(platelet derived growth factor receptor alpha,PDGFRA)、细胞周期蛋白依赖性激酶 6(cyclin⁃dependent kinase6,CDK6)和细胞周期蛋白 D2(cyclin D2,CCND2)的扩增,以及CDK抑制剂2A (cyclin ⁃ dependent kinase inhibitor 2A,CDKN2A)的缺失。Mackay 等[60] 发现了这一亚型中的 AKT1 扩增,其已被证明在胶质瘤进展中发挥重要作用[61]。更重要的是,该课题组通过癌症靶标基因组(genomic identification of significant targets in cancer,GISTIC) 分析,确定了染色体4q31.3上FBXW7 基因的丢失,其所编码的泛素连接酶成分FBW7是一种经典的泛素⁃蛋白酶体系统(ubiquitin⁃proteasome system,UPS) 蛋白,可通过靶向降解癌蛋白发挥抑癌作用[62]。最近,Hu 等[63] 通过全外显子组测序(whole⁃exome se⁃quencing,WES)发现,H3 G34 DHG 中黏蛋白 16/17 (mucin 16/17,MUC16/17)的高频率突变可作为有利预后的一个预测指标。针对H3 G34 DHG分子特征的研究,不仅为揭示其发病机制指出方向,更提供了可能的治疗靶点。

  • 5 治疗与预后

  • H3 G34 DHG的治疗原则与其他高级别胶质瘤基本相同,应以手术为主,手术原则为最大程度的安全切除,术后辅以放化疗,也可以联合电场治疗[64]。对于70岁以下的患者,在保证安全的情况下,应尽早开始放疗,一般在术后3~6周开始[65]。推荐采用适形放疗(conformal radiation therapy,CRT),包括 3 维适形(3⁃ dimensional CRT,3D ⁃CRT)和调强放疗 (intensity modulated RT,IMRT)[64]。放疗联合替莫唑胺(temozolomide,TMZ)是 GBM 术后的标准治疗方案[66],目前也被应用于 H3 G34 DHG 患者中。该亚型常伴随MGMT启动子甲基化,理论上对烷化剂如 TMZ 更为敏感[67]。CeTeG/NOA⁃09 试验结果显示,对 MGMT 甲基化的 GBM 来说,TMZ+洛莫司汀(lo⁃ mustine,CCNU)与单纯TMZ相比显著改善了患者总生存期(overall survival,OS)[68],提示二联烷化剂疗法也可能使H3 G34 DHG患者获得更多受益。贝伐珠单抗在HGG中的应用尚存在较多争议,似乎并未如期望般改善患者预后,在使用时应谨慎[66]。目前仍缺乏针对 H3 G34 DHG 的化疗方案。Lucas 等[69] 的研究发现,H3 G34 DHG具有一系列影响CDK4/6⁃ cyclin D⁃p16INK4a ⁃Rb 通路的基因改变,因此 CDK4/6 抑制剂如阿贝西利(abemaciclib)可能具有一定的治疗作用。Sweha 等[70] 发现了H3 G34 DHG中的信号转导及转录激活子3(signal transducer and activa⁃ tor of transcription 3,STAT3)的高表达,并在小鼠模型中应用靶向抑制剂WP1066成功抑制肿瘤。最近的一项Ⅰ期临床试验中,研究者通过立体定向导管向患儿瘤内注射溶瘤性单纯疱疹病毒1型(herpes simplex virus type1,HSV⁃1)G207,取得了一定的疗效[71]

  • 尽管许多患者接受了手术与术后放化疗,H3 G34 DHG 的预后目前仍不乐观。其中位总生存期(me⁃ dian overall survival,mOS)为 12.0~36.2 个月[2672],2 年生存率仅为27.3%[60],迄今尚缺乏大样本远期随访数据。切除范围是影响预后的独立因素[53],因此第 1 次手术对患者至关重要。大部分研究认为 H3 G34 DHG 的预后略好于 H3 K27 中线胶质瘤[63],但 HERBY 试验的结果显示二者的生存率一样差[72]。最近,Vuong等[73] 的研究首次揭示了与G34R突变相比,G34V DHG 患者预后更差,mOS仅为9.95个月,这是第一项揭示G34R与G34V DHG之间临床差异的研究。该研究同时发现了 PDGFRA 扩增与表皮生长因子受体(epidermal growth factor receptor,EG⁃ FR)扩增也是H3 G34 DHG患者不良预后的重要预测指标。因此,靶向PDGFRA激酶的药物如克莱拉尼(crenolanib)[74]、多酪氨酸激酶抑制剂如达沙替尼 (dasatinib)或许可以延长这类患者的生存期。

  • 6 总结与展望

  • H3 G34 DHG好发于儿童,尽管临床少见,但预后不佳,目前仍未完全清楚这一肿瘤的发病机制。该亚型影像学表现多变,常规 MRI 可能难以诊断,容易误诊,诊断应结合MRS、PET,以及脑脊液检测等。治疗以手术和放化疗为主,但尚无针对性的大规模药物临床试验。该亚型的组织学异质性较大,确诊主要依靠分子病理。作为2021年WHO更新的一种恶性CNS肿瘤,临床医师应提高对该疾病的认识。

  • 参考文献

    • [1] WELLER M,WICK W,ALDAPE K,et al.Glioma[J].Nat Rev Dis Primers,2015,1:15017

    • [2] LAPOINTE S,PERRY A,BUTOWSKI N A.Primary brain tumours in adults[J].Lancet,2018,392(10145):432-446

    • [3] OSTROM Q T,DE BLANK P M,KRUCHKO C,et al.Al⁃ ex’s lemonade stand foundation infant and childhood pri⁃ mary brain and central nervous system tumors diagnosed in the United States in 2007 ⁃ 2011[J].Neuro Oncol,2015,16(Suppl 10):x1-x36

    • [4] LOUIS D N,PERRY A,WESSELING P,et al.The 2021 WHO classification of tumors of the central nervous sys⁃ tem:a summary[J].Neuro Oncol,2021,23(8):1231-1251

    • [5] ALDERA A P,GOVENDER D.Gene of the month:H3F3A and H3F3B[J].J Clin Pathol,2022,75(1):1-4

    • [6] RAY⁃GALLET D,ALMOUZNI G.The histone H3 family and its deposition pathways[M]//FANG D,HAN J.His⁃ tone mutations and cancer.Singapore;Springer Singa⁃ pore,2021:17-42

    • [7] KUMAR V C,PAI R.Genes of the month:H3.3 histone genes:H3F3A and H3F3B[J].J Clin Pathol,2021,74(12):753-758

    • [8] TROVATO M,PATIL V,GEHRE M,et al.Histone vari⁃ ant H3.3 mutations in defining the chromatin function in mammals[J].Cells,2020,9(12):2716

    • [9] MILLÁN ⁃ ZAMBRANO G,BURTON A,BANNISTER A J,et al.Histone post ⁃translational modifications ⁃ cause and consequence of genome function[J].Nat Rev Genet,2022,23(9):563-580

    • [10] SHI L,WEN H,SHI X.The histone variant H3.3 in tran⁃ scriptional regulation and human disease[J].J Mol Biol,2017,429(13):1934-1945

    • [11] TAGAMI H,RAY⁃GALLET D,ALMOUZNI G,et al.His⁃ tone H3.1 and H3.3 complexes mediate nucleosome as⁃ sembly pathways dependent or independent of DNA syn⁃ thesis[J].Cell,2004,116(1):51-61

    • [12] XIONG C,WEN Z,YU J,et al.UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis ⁃regulatory elements of genes in mouse ES cells[J].BMC Biol,2018,16(1):110

    • [13] HUANG X,LIU J,MA Q.Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines[J].FEBS Open Bio,2020,10(10):2182-2190

    • [14] VALENZUELA M,AMATO R,SGURA A,et al.The mul⁃ tiple facets of ATRX protein[J].Cancers,2021,13(9):2211

    • [15] MAHMUD I,LIAO D.DAXX in cancer:phenomena,pro⁃ cesses,mechanisms and regulation[J].Nucleic Acids Res,2019,47(15):7734-7752

    • [16] UDUGAMA M,HII L,GARVIE A,et al.Mutations inhib⁃ iting KDM4B drive ALT activation in ATRX⁃mutated glio⁃ blastomas[J].Nat Commun,2021,12(1):2584

    • [17] SCHWARTZENTRUBER J,KORSHUNOV A,LIU X Y,et al.Driver mutations in histone H3.3 and chromatin re⁃ modelling genes in paediatric glioblastoma[J].Nature,2012,482(7384):226-231

    • [18] LOUIS D N,WESSELING P,ALDAPE K,et al.cIMPACT⁃ NOW update 6:new entity and diagnostic principle rec⁃ ommendations of the cIMPACT⁃Utrecht meeting on future CNS tumor classification and grading[J].Brain Pathol,2020,30(4):844-856

    • [19] LOWE B R,MAXHAM L A,HAMEY J J,et al.Histone H3 mutations:an updated view of their role in chromatin deregulation and cancer[J].Cancers,2019,11(5):660

    • [20] WU G,BRONISCER A,MCEACHRON T A,et al.Somat⁃ ic histone H3 alterations in pediatric diffuse intrinsic pon⁃ tine gliomas and non ⁃ brainstem glioblastomas[J].Nat Genet,2012,44(3):251-253

    • [21] STURM D,WITT H,HOVESTADT V,et al.Hotspot mu⁃ tations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma[J].Cancer Cell,2012,22(4):425-437

    • [22] KAY M D,PARIURY H E,PERRY A,et al.Extracranial metastases from glioblastoma with primitive neuronal com⁃ ponents on FDG PET/CT[J].Clin Nucl Med,2020,45(3):e162-e164

    • [23] MOHIUDDIN S,MARAKA S,USMAN BAIG M,et al.Case series of diffuse extraneural metastasis in H3F3A mutant high⁃grade gliomas:clinical,molecular phenotype and literature review[J].J Clin Neurosci,2021,89:405-411

    • [24] KORSHUNOV A,RYZHOVA M,HOVESTADT V,et al.Integrated analysis of pediatric glioblastoma reveals a sub⁃ set of biologically favorable tumors with associated molec⁃ ular prognostic markers[J].Acta Neuropathol,2015,129(5):669-678

    • [25] NEUMANN J E,DOROSTKAR M M,KORSHUNOV A,et al.Distinct histomorphology in molecular subgroups of glioblastomas in young patients[J].J Neuropathol Exp Neurol,2016,75(5):408-414

    • [26] ROUX A,PALLUD J,SAFFROY R,et al.High⁃grade gli⁃ omas in adolescents and young adults highlight histomo⁃ lecular differences from their adult and pediatric counter⁃ parts[J].Neuro Oncol,2020,22(8):1190-1202

    • [27] LIM K Y,WON J K,PARK C K,et al.H3 G34⁃mutant high⁃grade glioma[J].Brain Tumor Pathol,2021,38(1):4-13

    • [28] YOSHIMOTO K,HATAE R,SANGATSUDA Y,et al.Prevalence and clinicopathological features of H3.3 G34⁃ mutant high ⁃ grade gliomas:a retrospective study of 411 consecutive glioma cases in a single institution[J].Brain Tumor Pathol,2017,34(3):103-112

    • [29] 王玮,王雷明,卢德宏,等.伴有H3 G34R突变的高级别胶质瘤临床病理学观察[J].中华病理学杂志,2020,49(12):1267-1271

    • [30] KHAZAEI S,DE JAY N,DESHMUKH S,et al.H3.3 G34W promotes growth and impedes differentiation of os⁃ teoblast⁃like mesenchymal progenitors in giant cell tumor of bone[J].Cancer Discov,2020,10(12):1968-1987

    • [31] COLEMAN C,STOLLER S,GROTZER M,et al.Pediat⁃ ric hemispheric high ⁃ grade glioma:targeting the future [J].Cancer Metastasis Rev,2020,39(1):245-260

    • [32] STOCCO C,PILOTTO C,PASSONE E,et al.Presentation and symptom interval in children with central nervous sys⁃ tem tumors.a single ⁃ center experience[J].Childs Nerv Syst,2017,33(12):2109-2116

    • [33] SMITS M.MRI biomarkers in neuro⁃oncology[J].Nat Rev Neurol,2021,17(8):486-500

    • [34] PUNTONET J,DANGOULOFF⁃ROS V,SAFFROY R,et al.Historadiological correlations in high ⁃ grade glioma with the histone 3.3 G34R mutation[J].J Neuroradiol,2018,45(5):316-322

    • [35] ONISHI S,AMATYA V J,KARLOWEE V,et al.Radio⁃ logical and immunostaining characteristics of H3.3 G34R⁃ mutant glioma:a report of 3 cases and review of the litera⁃ ture[J].Pediatr Neurosurg,2020,55(5):319-325

    • [36] KUROKAWA R,BABA A,KUROKAWA M,et al.Neuro⁃ imaging features of diffuse hemispheric glioma,H3 G34⁃ mutant:a case series and systematic review[J].J Neuro⁃ imaging,2021,32(1):17-27

    • [37] 唐文天,张梓枫,尹建新,等.常规MRI特征在弥漫性星形细胞瘤IDH基因突变预测中的临床价值[J].南京医科大学学报(自然科学版),2022,42(3):376-381

    • [38] OVERCAST W B,DAVIS K M,HO C Y,et al.Advanced imaging techniques for neuro ⁃oncologic tumor diagnosis,with an emphasis on PET ⁃ MRI imaging of malignant brain tumors[J].Curr Oncol Rep,2021,23(3):34

    • [39] VETTERMANN F J,FELSBERG J,REIFENBERGER G,et al.Characterization of diffuse gliomas with histone H3⁃ G34 mutation by MRI and dynamic 18F⁃FET PET[J].Clin Nucl Med,2018,43(12):895-898

    • [40] MARNER L,LUNDEMANN M,SEHESTED A,et al.Di⁃ agnostic accuracy and clinical impact of 18FFET PET in childhood CNS tumors[J].Neuro Oncol,2021,23(12):2107-2116

    • [41] 龚俊杰,刘秀秀,王平,等.代谢组学在胶质母细胞瘤相关研究中的应用[J].南京医科大学学报(自然科学版),2021,41(2):296-305

    • [42] MAYERHOEFER M E,MATERKA A,LANGS G,et al.Introduction to radiomics[J].J Nucl Med,2020,61(4):488-495

    • [43] ZHAO J,HUANG Y,SONG Y,et al.Diagnostic accuracy and potential covariates for machine learning to identify IDH mutations in glioma patients:evidence from a meta ⁃ analysis[J].Eur Radiol,2020,30(8):4664-4674

    • [44] GUO W,SHE D,XING Z,et al.Multiparametric MRI ⁃ based radiomics model for predicting H3 K27M mutant status in diffuse midline glioma:a comparative study across different sequences and machine learning tech⁃ niques[J].Front Oncol,2022,12:796583

    • [45] HOHM A,KARREMANN M,GIELEN G H,et al.Mag⁃ netic resonance imaging characteristics of molecular sub⁃ groups in pediatric H3 K27M mutant diffuse midline glio⁃ ma[J].Clin Neuroradiol,2022,32(1):249-258

    • [46] LASOCKI A,ANJARI M,ÖRS KOKURCAN S,et al.Con⁃ ventional MRI features of adult diffuse glioma molecular subtypes:a systematic review[J].Neuroradiology,2021,63(3):353-362

    • [47] GONÇALVES F G,VIAENE A N,VOSSOUGH A.Ad⁃ vanced magnetic resonance imaging in pediatric glioblas⁃ tomas[J].Front Neurol,2021,12:733323

    • [48] BARRAGáN ⁃PéREZ E J,ALTAMIRANO ⁃VERGARA C E,ALVAREZ ⁃AMADO D E,et al.The role of time as a prognostic factor in pediatric brain tumors:a multivariate survival analysis[J].Pathol Oncol Res,2020,26(4):2693-2701

    • [49] PICART T,BARRITAULT M,PONCET D,et al.Charac⁃ teristics of diffuse hemispheric gliomas,H3 G34 ⁃ mutant in adults[J].Neurooncol Adv,2021,3(1):vdab061

    • [50] HODGSON J M,DOUCH C,HARTLEY L,et al.Problem solving in clinical practice:an unusual cause of multifo⁃ cal brain lesions[J].Arch Dis Child Educ Pract Ed,2021,106(5):299-303

    • [51] HUANG T Y,PIUNTI A,LULLA R R,et al.Detection of histone H3 mutations in cerebrospinal fluid ⁃ derived tu⁃ mor DNA from children with diffuse midline glioma[J].Acta Neuropathol Commun,2017,5(1):28

    • [52] GESSI M,GIELEN G H,HAMMES J,et al.H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system(CNS⁃PNET)and pediatric glio⁃ blastomas:possible diagnostic and therapeutic implica⁃ tions?[J].J Neurooncol,2013,112(1):67-72

    • [53] WANG L,SHAO L,LI H,et al.Histone H3.3 G34⁃mutant diffuse gliomas in adults[J].Am J Surg Pathol,2022,46(2):249-257

    • [54] GILANI A,KLEINSCHMIDT⁃DEMASTERS B K.Morpho⁃ logical diversity in H3G34 ⁃ mutant high ⁃ grade gliomas:ganglionic and epithelioid features[J].Clin Neuropathol,2021,40(1):4-10

    • [55] MORRIS M,DRISCOLL M,HENSON J W,et al.Low ⁃ grade gemistocytic morphology in H3 G34R ⁃Mutant glio⁃ mas and concurrent K27M mutation:clinicopathologic findings[J].J Neuropathol Exp Neurol,2020,79(10):1038-1043

    • [56] SASAKI S,TOMOMASA R,NOBUSAWA S,et al.Ana⁃ plastic pleomorphic xanthoastrocytoma associated with an H3G34 mutation:a case report with review of literature [J].Brain Tumor Pathol,2019,36(4):169-173

    • [57] ANDREIUOLO F,LISNER T,ZLOCHA J,et al.H3F3A⁃ G34R mutant high grade neuroepithelial neoplasms with glial and dysplastic ganglion cell components[J].Acta Neuropathol Commun,2019,7(1):78

    • [58] KORSHUNOV A,CAPPER D,REUSS D,et al.Histologi⁃ cally distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single no⁃ sologic entity[J].Acta neuropathol,2016,131(1):137-146

    • [59] 邹婉婧,崔云,何艳姣,等.H3 G34突变型弥漫性半球胶质瘤临床和病理学特征分析[J].中华神经外科杂志,2021,37(11):1090-1096

    • [60] MACKAY A,BURFORD A,CARVALHO D,et al.Inte⁃ grated molecular meta ⁃analysis of 1,000 pediatric high ⁃ grade and diffuse intrinsic pontine glioma[J].Cancer Cell,2017,32(4):520-537

    • [61] WANG Y,XIE X,LI S,et al.Co⁃overexpression of RIOK1 and AKT1 as a prognostic risk factor in glioma[J].J Can⁃ cer,2021,12(19):5745-5752

    • [62] DAVIS R J,WELCKER M,CLURMAN B E.Tumor sup⁃ pression by the Fbw7 ubiquitin ligase:mechanisms and opportunities[J].Cancer Cell,2014,26(4):455-464

    • [63] HU W,DUAN H,ZHONG S,et al.High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma,H3 G34⁃mutant:a glimmer of hope?[J].J Transl Med,2022,20(1):64

    • [64] NABORS L B,PORTNOW J,AHLUWALIA M,et al.Cen⁃ tral nervous system cancers,version 3.2020,NCCN clini⁃ cal practice guidelines in oncology[J].J Nati Comp Canc Netw,2020,18(11):1537-1570

    • [65] SULMAN E P,ISMAILA N,ARMSTRONG T S,et al.Ra⁃ diation therapy for glioblastoma:american society of clini⁃ cal oncology clinical practice guideline endorsement of the American Society for radiation oncology guideline[J].J Clin Oncol,2017,35(3):361-369

    • [66] WELLER M,VAN DEN BENT M,PREUSSER M,et al.EANO guidelines on the diagnosis and treatment of dif⁃ fuse gliomas of adulthood[J].Nat Rev Clin Oncol,2021,18(3):170-186

    • [67] DONSON A M,ADDO ⁃YOBO S O,HANDLER M H,et al.MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glio⁃ blastoma[J].Pediatr Blood Cancer,2007,48(4):403-407

    • [68] WELLER J,TZARIDIS T,MACK F,et al.Health⁃related quality of life and neurocognitive functioning with lomus⁃ tine ⁃ temozolomide versus temozolomide in patients with newly diagnosed,MGMT ⁃ methylated glioblastoma(Ce⁃ TeG/NOA ⁃ 09):a randomised,multicentre,open ⁃ label,phase 3 trial[J].Lancet Oncol,2019,20(10):1444-1453

    • [69] LUCAS C G,MUELLER S,REDDY A,et al.Diffuse hemi⁃ spheric glioma,H3 G34⁃mutant:genomic landscape of a new tumor entity and prospects for targeted therapy[J].Neurooncol,2021,23(11):1974-1976

    • [70] SWEHA S R,CHUNG C,NATARAJAN S K,et al.Epige⁃ netically defined therapeutic targeting in H3.3G34R/V high ⁃grade gliomas[J].Sci transl med,2021,13(615):eabf7860

    • [71] FRIEDMAN G K,JOHNSTON J M,BAG A K,et al.On⁃ colytic HSV⁃1 G207 immunovirotherapy for pediatric high ⁃grade gliomas[J].N Engl J Med,2021,384(17):1613-1622

    • [72] MACKAY A,BURFORD A,MOLINARI V,et al.Molecu⁃ lar,pathological,radiological,and immune profiling of non⁃ brainstem pediatric high ⁃ grade glioma from the HERBY phase Ⅱ randomized trial[J].Cancer Cell,2018,33(5):829-842

    • [73] VUONG H G,LE H T,DUNN I F.The prognostic signifi⁃ cance of further genotyping H3G34 diffuse hemispheric gliomas[J].Cancer,2022,128(10):1907-1912

    • [74] TINKLE C L,BRONISCER A,CHIANG J,et al.Phase I study using crenolanib to target PDGFR kinase in chil⁃ dren and young adults with newly diagnosed DIPG or re⁃ current high⁃grade glioma,including DIPG[J].Neuroon⁃ col Adv,2021,3(1):vdab179

  • 参考文献

    • [1] WELLER M,WICK W,ALDAPE K,et al.Glioma[J].Nat Rev Dis Primers,2015,1:15017

    • [2] LAPOINTE S,PERRY A,BUTOWSKI N A.Primary brain tumours in adults[J].Lancet,2018,392(10145):432-446

    • [3] OSTROM Q T,DE BLANK P M,KRUCHKO C,et al.Al⁃ ex’s lemonade stand foundation infant and childhood pri⁃ mary brain and central nervous system tumors diagnosed in the United States in 2007 ⁃ 2011[J].Neuro Oncol,2015,16(Suppl 10):x1-x36

    • [4] LOUIS D N,PERRY A,WESSELING P,et al.The 2021 WHO classification of tumors of the central nervous sys⁃ tem:a summary[J].Neuro Oncol,2021,23(8):1231-1251

    • [5] ALDERA A P,GOVENDER D.Gene of the month:H3F3A and H3F3B[J].J Clin Pathol,2022,75(1):1-4

    • [6] RAY⁃GALLET D,ALMOUZNI G.The histone H3 family and its deposition pathways[M]//FANG D,HAN J.His⁃ tone mutations and cancer.Singapore;Springer Singa⁃ pore,2021:17-42

    • [7] KUMAR V C,PAI R.Genes of the month:H3.3 histone genes:H3F3A and H3F3B[J].J Clin Pathol,2021,74(12):753-758

    • [8] TROVATO M,PATIL V,GEHRE M,et al.Histone vari⁃ ant H3.3 mutations in defining the chromatin function in mammals[J].Cells,2020,9(12):2716

    • [9] MILLÁN ⁃ ZAMBRANO G,BURTON A,BANNISTER A J,et al.Histone post ⁃translational modifications ⁃ cause and consequence of genome function[J].Nat Rev Genet,2022,23(9):563-580

    • [10] SHI L,WEN H,SHI X.The histone variant H3.3 in tran⁃ scriptional regulation and human disease[J].J Mol Biol,2017,429(13):1934-1945

    • [11] TAGAMI H,RAY⁃GALLET D,ALMOUZNI G,et al.His⁃ tone H3.1 and H3.3 complexes mediate nucleosome as⁃ sembly pathways dependent or independent of DNA syn⁃ thesis[J].Cell,2004,116(1):51-61

    • [12] XIONG C,WEN Z,YU J,et al.UBN1/2 of HIRA complex is responsible for recognition and deposition of H3.3 at cis ⁃regulatory elements of genes in mouse ES cells[J].BMC Biol,2018,16(1):110

    • [13] HUANG X,LIU J,MA Q.Prohibitin participates in the HIRA complex to promote cell metastasis in breast cancer cell lines[J].FEBS Open Bio,2020,10(10):2182-2190

    • [14] VALENZUELA M,AMATO R,SGURA A,et al.The mul⁃ tiple facets of ATRX protein[J].Cancers,2021,13(9):2211

    • [15] MAHMUD I,LIAO D.DAXX in cancer:phenomena,pro⁃ cesses,mechanisms and regulation[J].Nucleic Acids Res,2019,47(15):7734-7752

    • [16] UDUGAMA M,HII L,GARVIE A,et al.Mutations inhib⁃ iting KDM4B drive ALT activation in ATRX⁃mutated glio⁃ blastomas[J].Nat Commun,2021,12(1):2584

    • [17] SCHWARTZENTRUBER J,KORSHUNOV A,LIU X Y,et al.Driver mutations in histone H3.3 and chromatin re⁃ modelling genes in paediatric glioblastoma[J].Nature,2012,482(7384):226-231

    • [18] LOUIS D N,WESSELING P,ALDAPE K,et al.cIMPACT⁃ NOW update 6:new entity and diagnostic principle rec⁃ ommendations of the cIMPACT⁃Utrecht meeting on future CNS tumor classification and grading[J].Brain Pathol,2020,30(4):844-856

    • [19] LOWE B R,MAXHAM L A,HAMEY J J,et al.Histone H3 mutations:an updated view of their role in chromatin deregulation and cancer[J].Cancers,2019,11(5):660

    • [20] WU G,BRONISCER A,MCEACHRON T A,et al.Somat⁃ ic histone H3 alterations in pediatric diffuse intrinsic pon⁃ tine gliomas and non ⁃ brainstem glioblastomas[J].Nat Genet,2012,44(3):251-253

    • [21] STURM D,WITT H,HOVESTADT V,et al.Hotspot mu⁃ tations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma[J].Cancer Cell,2012,22(4):425-437

    • [22] KAY M D,PARIURY H E,PERRY A,et al.Extracranial metastases from glioblastoma with primitive neuronal com⁃ ponents on FDG PET/CT[J].Clin Nucl Med,2020,45(3):e162-e164

    • [23] MOHIUDDIN S,MARAKA S,USMAN BAIG M,et al.Case series of diffuse extraneural metastasis in H3F3A mutant high⁃grade gliomas:clinical,molecular phenotype and literature review[J].J Clin Neurosci,2021,89:405-411

    • [24] KORSHUNOV A,RYZHOVA M,HOVESTADT V,et al.Integrated analysis of pediatric glioblastoma reveals a sub⁃ set of biologically favorable tumors with associated molec⁃ ular prognostic markers[J].Acta Neuropathol,2015,129(5):669-678

    • [25] NEUMANN J E,DOROSTKAR M M,KORSHUNOV A,et al.Distinct histomorphology in molecular subgroups of glioblastomas in young patients[J].J Neuropathol Exp Neurol,2016,75(5):408-414

    • [26] ROUX A,PALLUD J,SAFFROY R,et al.High⁃grade gli⁃ omas in adolescents and young adults highlight histomo⁃ lecular differences from their adult and pediatric counter⁃ parts[J].Neuro Oncol,2020,22(8):1190-1202

    • [27] LIM K Y,WON J K,PARK C K,et al.H3 G34⁃mutant high⁃grade glioma[J].Brain Tumor Pathol,2021,38(1):4-13

    • [28] YOSHIMOTO K,HATAE R,SANGATSUDA Y,et al.Prevalence and clinicopathological features of H3.3 G34⁃ mutant high ⁃ grade gliomas:a retrospective study of 411 consecutive glioma cases in a single institution[J].Brain Tumor Pathol,2017,34(3):103-112

    • [29] 王玮,王雷明,卢德宏,等.伴有H3 G34R突变的高级别胶质瘤临床病理学观察[J].中华病理学杂志,2020,49(12):1267-1271

    • [30] KHAZAEI S,DE JAY N,DESHMUKH S,et al.H3.3 G34W promotes growth and impedes differentiation of os⁃ teoblast⁃like mesenchymal progenitors in giant cell tumor of bone[J].Cancer Discov,2020,10(12):1968-1987

    • [31] COLEMAN C,STOLLER S,GROTZER M,et al.Pediat⁃ ric hemispheric high ⁃ grade glioma:targeting the future [J].Cancer Metastasis Rev,2020,39(1):245-260

    • [32] STOCCO C,PILOTTO C,PASSONE E,et al.Presentation and symptom interval in children with central nervous sys⁃ tem tumors.a single ⁃ center experience[J].Childs Nerv Syst,2017,33(12):2109-2116

    • [33] SMITS M.MRI biomarkers in neuro⁃oncology[J].Nat Rev Neurol,2021,17(8):486-500

    • [34] PUNTONET J,DANGOULOFF⁃ROS V,SAFFROY R,et al.Historadiological correlations in high ⁃ grade glioma with the histone 3.3 G34R mutation[J].J Neuroradiol,2018,45(5):316-322

    • [35] ONISHI S,AMATYA V J,KARLOWEE V,et al.Radio⁃ logical and immunostaining characteristics of H3.3 G34R⁃ mutant glioma:a report of 3 cases and review of the litera⁃ ture[J].Pediatr Neurosurg,2020,55(5):319-325

    • [36] KUROKAWA R,BABA A,KUROKAWA M,et al.Neuro⁃ imaging features of diffuse hemispheric glioma,H3 G34⁃ mutant:a case series and systematic review[J].J Neuro⁃ imaging,2021,32(1):17-27

    • [37] 唐文天,张梓枫,尹建新,等.常规MRI特征在弥漫性星形细胞瘤IDH基因突变预测中的临床价值[J].南京医科大学学报(自然科学版),2022,42(3):376-381

    • [38] OVERCAST W B,DAVIS K M,HO C Y,et al.Advanced imaging techniques for neuro ⁃oncologic tumor diagnosis,with an emphasis on PET ⁃ MRI imaging of malignant brain tumors[J].Curr Oncol Rep,2021,23(3):34

    • [39] VETTERMANN F J,FELSBERG J,REIFENBERGER G,et al.Characterization of diffuse gliomas with histone H3⁃ G34 mutation by MRI and dynamic 18F⁃FET PET[J].Clin Nucl Med,2018,43(12):895-898

    • [40] MARNER L,LUNDEMANN M,SEHESTED A,et al.Di⁃ agnostic accuracy and clinical impact of 18FFET PET in childhood CNS tumors[J].Neuro Oncol,2021,23(12):2107-2116

    • [41] 龚俊杰,刘秀秀,王平,等.代谢组学在胶质母细胞瘤相关研究中的应用[J].南京医科大学学报(自然科学版),2021,41(2):296-305

    • [42] MAYERHOEFER M E,MATERKA A,LANGS G,et al.Introduction to radiomics[J].J Nucl Med,2020,61(4):488-495

    • [43] ZHAO J,HUANG Y,SONG Y,et al.Diagnostic accuracy and potential covariates for machine learning to identify IDH mutations in glioma patients:evidence from a meta ⁃ analysis[J].Eur Radiol,2020,30(8):4664-4674

    • [44] GUO W,SHE D,XING Z,et al.Multiparametric MRI ⁃ based radiomics model for predicting H3 K27M mutant status in diffuse midline glioma:a comparative study across different sequences and machine learning tech⁃ niques[J].Front Oncol,2022,12:796583

    • [45] HOHM A,KARREMANN M,GIELEN G H,et al.Mag⁃ netic resonance imaging characteristics of molecular sub⁃ groups in pediatric H3 K27M mutant diffuse midline glio⁃ ma[J].Clin Neuroradiol,2022,32(1):249-258

    • [46] LASOCKI A,ANJARI M,ÖRS KOKURCAN S,et al.Con⁃ ventional MRI features of adult diffuse glioma molecular subtypes:a systematic review[J].Neuroradiology,2021,63(3):353-362

    • [47] GONÇALVES F G,VIAENE A N,VOSSOUGH A.Ad⁃ vanced magnetic resonance imaging in pediatric glioblas⁃ tomas[J].Front Neurol,2021,12:733323

    • [48] BARRAGáN ⁃PéREZ E J,ALTAMIRANO ⁃VERGARA C E,ALVAREZ ⁃AMADO D E,et al.The role of time as a prognostic factor in pediatric brain tumors:a multivariate survival analysis[J].Pathol Oncol Res,2020,26(4):2693-2701

    • [49] PICART T,BARRITAULT M,PONCET D,et al.Charac⁃ teristics of diffuse hemispheric gliomas,H3 G34 ⁃ mutant in adults[J].Neurooncol Adv,2021,3(1):vdab061

    • [50] HODGSON J M,DOUCH C,HARTLEY L,et al.Problem solving in clinical practice:an unusual cause of multifo⁃ cal brain lesions[J].Arch Dis Child Educ Pract Ed,2021,106(5):299-303

    • [51] HUANG T Y,PIUNTI A,LULLA R R,et al.Detection of histone H3 mutations in cerebrospinal fluid ⁃ derived tu⁃ mor DNA from children with diffuse midline glioma[J].Acta Neuropathol Commun,2017,5(1):28

    • [52] GESSI M,GIELEN G H,HAMMES J,et al.H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system(CNS⁃PNET)and pediatric glio⁃ blastomas:possible diagnostic and therapeutic implica⁃ tions?[J].J Neurooncol,2013,112(1):67-72

    • [53] WANG L,SHAO L,LI H,et al.Histone H3.3 G34⁃mutant diffuse gliomas in adults[J].Am J Surg Pathol,2022,46(2):249-257

    • [54] GILANI A,KLEINSCHMIDT⁃DEMASTERS B K.Morpho⁃ logical diversity in H3G34 ⁃ mutant high ⁃ grade gliomas:ganglionic and epithelioid features[J].Clin Neuropathol,2021,40(1):4-10

    • [55] MORRIS M,DRISCOLL M,HENSON J W,et al.Low ⁃ grade gemistocytic morphology in H3 G34R ⁃Mutant glio⁃ mas and concurrent K27M mutation:clinicopathologic findings[J].J Neuropathol Exp Neurol,2020,79(10):1038-1043

    • [56] SASAKI S,TOMOMASA R,NOBUSAWA S,et al.Ana⁃ plastic pleomorphic xanthoastrocytoma associated with an H3G34 mutation:a case report with review of literature [J].Brain Tumor Pathol,2019,36(4):169-173

    • [57] ANDREIUOLO F,LISNER T,ZLOCHA J,et al.H3F3A⁃ G34R mutant high grade neuroepithelial neoplasms with glial and dysplastic ganglion cell components[J].Acta Neuropathol Commun,2019,7(1):78

    • [58] KORSHUNOV A,CAPPER D,REUSS D,et al.Histologi⁃ cally distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single no⁃ sologic entity[J].Acta neuropathol,2016,131(1):137-146

    • [59] 邹婉婧,崔云,何艳姣,等.H3 G34突变型弥漫性半球胶质瘤临床和病理学特征分析[J].中华神经外科杂志,2021,37(11):1090-1096

    • [60] MACKAY A,BURFORD A,CARVALHO D,et al.Inte⁃ grated molecular meta ⁃analysis of 1,000 pediatric high ⁃ grade and diffuse intrinsic pontine glioma[J].Cancer Cell,2017,32(4):520-537

    • [61] WANG Y,XIE X,LI S,et al.Co⁃overexpression of RIOK1 and AKT1 as a prognostic risk factor in glioma[J].J Can⁃ cer,2021,12(19):5745-5752

    • [62] DAVIS R J,WELCKER M,CLURMAN B E.Tumor sup⁃ pression by the Fbw7 ubiquitin ligase:mechanisms and opportunities[J].Cancer Cell,2014,26(4):455-464

    • [63] HU W,DUAN H,ZHONG S,et al.High frequency of PDGFRA and MUC family gene mutations in diffuse hemispheric glioma,H3 G34⁃mutant:a glimmer of hope?[J].J Transl Med,2022,20(1):64

    • [64] NABORS L B,PORTNOW J,AHLUWALIA M,et al.Cen⁃ tral nervous system cancers,version 3.2020,NCCN clini⁃ cal practice guidelines in oncology[J].J Nati Comp Canc Netw,2020,18(11):1537-1570

    • [65] SULMAN E P,ISMAILA N,ARMSTRONG T S,et al.Ra⁃ diation therapy for glioblastoma:american society of clini⁃ cal oncology clinical practice guideline endorsement of the American Society for radiation oncology guideline[J].J Clin Oncol,2017,35(3):361-369

    • [66] WELLER M,VAN DEN BENT M,PREUSSER M,et al.EANO guidelines on the diagnosis and treatment of dif⁃ fuse gliomas of adulthood[J].Nat Rev Clin Oncol,2021,18(3):170-186

    • [67] DONSON A M,ADDO ⁃YOBO S O,HANDLER M H,et al.MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glio⁃ blastoma[J].Pediatr Blood Cancer,2007,48(4):403-407

    • [68] WELLER J,TZARIDIS T,MACK F,et al.Health⁃related quality of life and neurocognitive functioning with lomus⁃ tine ⁃ temozolomide versus temozolomide in patients with newly diagnosed,MGMT ⁃ methylated glioblastoma(Ce⁃ TeG/NOA ⁃ 09):a randomised,multicentre,open ⁃ label,phase 3 trial[J].Lancet Oncol,2019,20(10):1444-1453

    • [69] LUCAS C G,MUELLER S,REDDY A,et al.Diffuse hemi⁃ spheric glioma,H3 G34⁃mutant:genomic landscape of a new tumor entity and prospects for targeted therapy[J].Neurooncol,2021,23(11):1974-1976

    • [70] SWEHA S R,CHUNG C,NATARAJAN S K,et al.Epige⁃ netically defined therapeutic targeting in H3.3G34R/V high ⁃grade gliomas[J].Sci transl med,2021,13(615):eabf7860

    • [71] FRIEDMAN G K,JOHNSTON J M,BAG A K,et al.On⁃ colytic HSV⁃1 G207 immunovirotherapy for pediatric high ⁃grade gliomas[J].N Engl J Med,2021,384(17):1613-1622

    • [72] MACKAY A,BURFORD A,MOLINARI V,et al.Molecu⁃ lar,pathological,radiological,and immune profiling of non⁃ brainstem pediatric high ⁃ grade glioma from the HERBY phase Ⅱ randomized trial[J].Cancer Cell,2018,33(5):829-842

    • [73] VUONG H G,LE H T,DUNN I F.The prognostic signifi⁃ cance of further genotyping H3G34 diffuse hemispheric gliomas[J].Cancer,2022,128(10):1907-1912

    • [74] TINKLE C L,BRONISCER A,CHIANG J,et al.Phase I study using crenolanib to target PDGFR kinase in chil⁃ dren and young adults with newly diagnosed DIPG or re⁃ current high⁃grade glioma,including DIPG[J].Neuroon⁃ col Adv,2021,3(1):vdab179