Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course

被引：93

作者：

Wefers, Annika K. ^{[1
,2
,3
]}

Stichel, Damian ^{[1
,2
]}

Schrimpf, Daniel ^{[1
,2
]}

Coras, Roland ^{[4
]}

Pages, Melanie ^{[5
]}

Tauziede-Espariat, Arnault ^{[5
]}

Varlet, Pascale ^{[5
]}

Schwarz, Daniel ^{[6
,7
]}

Soylemezoglu, Figen ^{[8
]}

Pohl, Ute ^{[9
,10
,11
]}

Pimentel, Jose ^{[12
,13
]}

Meyer, Jochen ^{[1
,2
]}

Hewer, Ekkehard ^{[14
]}

Japp, Anna ^{[15
]}

Joshi, Abhijit ^{[16
]}

Reuss, David E. ^{[1
,2
]}

Reinhardt, Annekathrin ^{[1
,2
]}

Sievers, Philipp ^{[1
,2
]}

Casalini, M. Belen ^{[1
,2
]}

Ebrahimi, Azadeh ^{[1
,2
]}

Huang, Kristin ^{[1
,2
]}

Koelsche, Christian ^{[1
,17
]}

Low, Hu Liang ^{[18
]}

Rebelo, Olinda ^{[19
]}

Marnoto, Dina ^{[19
]}

Becker, Albert J. ^{[15
]}

Staszewski, Ori ^{[20
]}

Mittelbronn, Michel ^{[21
,22
,23
,24
,25
]}

Hasselblatt, Martin ^{[26
]}

Schittenhelm, Jens ^{[27
,28
]}

Cheesman, Edmund ^{[29
]}

de Oliveira, Ricardo Santos ^{[30
]}

Queiroz, Rosane Gomes P. ^{[31
]}

Valera, Elvis Terci ^{[31
]}

Hans, Volkmar H. ^{[32
,33
]}

Korshunov, Andrey ^{[1
,2
]}

Olar, Adriana ^{[34
,35
,36
]}

Ligon, Keith L. ^{[37
]}

Pfister, Stefan M. ^{[3
,38
,39
,40
]}

Jaunmuktane, Zane ^{[41
,42
]}

Brandner, Sebastian ^{[42
,43
]}

Tatevossian, Ruth G. ^{[44
]}

Ellison, David W. ^{[44
]}

Jacques, Thomas S. ^{[45
]}

Honavar, Mrinalini ^{[46
]}

Aronica, Eleonora ^{[47
]}

Thom, Maria ^{[41
]}

Sahm, Felix ^{[1
,2
,3
]}

von Deimling, Andreas ^{[1
,2
]}

Jones, David T. W. ^{[3
,48
]}

机构：

[1] Univ Hosp Heidelberg, Inst Pathol, Dept Neuropathol, Heidelberg, Germany

[2] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, German Canc Consortium DKTK, Heidelberg, Germany

[3] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany

[4] Univ Hosp Erlangen, Dept Neuropathol, Erlangen, Germany

[5] Descartes Univ, St Anne Hosp, Dept Neuropathol, Paris, France

[6] Univ Hosp Heidelberg, Dept Neuroradiol, Heidelberg, Germany

[7] German Canc Res Ctr, Dept Radiol, Heidelberg, Germany

[8] Hacettepe Univ, Dept Pathol, Fac Med, Ankara, Turkey

[9] Queens Hosp BHRUT, Dept Cellular Pathol, Romford, Essex, England

[10] Queen Elizabeth Hosp, Dept Cellular Pathol, Birmingham, W Midlands, England

[11] Univ Hosp Birmingham, Birmingham, W Midlands, England

[12] Hosp Santa Maria CHULN, Dept Neurosci & Mental Hlth, Lab Neuropathol, EPE, Lisbon, Portugal

[13] Univ Lisbon, Fac Med, Lisbon, Portugal

[14] Univ Bern, Inst Pathol, Bern, Switzerland

[15] Univ Bonn, Dept Neuropathol, Bonn, Germany

[16] Royal Victoria Infirm, Dept Neuropathol, Newcastle Upon Tyne, Tyne & Wear, England

[17] Univ Hosp Heidelberg, Inst Pathol, Dept Gen Pathol, Heidelberg, Germany

[18] Queens Hosp BHRUT, Dept Neurosurg, Romford, Essex, England

[19] Ctr Hosp Univ Coimbra, Neuropathol Unit, Coimbra, Portugal

[20] Univ Freiburg, Inst Neuropathol, Freiburg, Germany

[21] Univ Frankfurt Main, Edinger Inst, Inst Neurol, Frankfurt, Germany

[22] Luxembourg Ctr Neuropathol LCNP, Dudelange, Luxembourg

[23] NCP, LNS, Dudelange, Luxembourg

[24] Univ Luxembourg, LCSB, Esch Sur Alzette, Luxembourg

[25] Luxembourg Inst Hlth, Dept Oncol DONC, Luxembourg City, Luxembourg

[26] Univ Hosp Munster, Inst Neuropathol, Munster, Germany

[27] Univ Hosp Tubingen, Inst Pathol & Neuropathol, Dept Neuropathol, Tubingen, Germany

[28] Univ Hosp Tubingen, Ctr CNS Tumours, Comprehens Canc Ctr Tubingen Stuttgart, Tubingen, Germany

[29] Royal Manchester Childrens Hosp Manchester, Dept Paediat Histopathol, Manchester, Lancs, England

[30] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Surg & Anat, Div Pediat Neurosurg, Sao Paulo, SP, Brazil

[31] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo, SP, Brazil

[32] Dietrich Bonhoeffer Klinikum, Inst Klin Pathol, Abt Neuropathol, Neubrandenburg, Germany

[33] Evangel Klinikum Bethel gGmbH, Inst Neuropathol, Bielefeld, Germany

[34] Med Univ South Carolina, Dept Pathol & Lab Med, Charleston, SC 29425 USA

[35] Med Univ South Carolina, Dept Neurosurg, Charleston, SC 29425 USA

[36] Hollings Canc Ctr, Charleston, SC USA

[37] Harvard Med Sch, Dana Farber Brigham & Womens Canc Ctr, Dept Oncol Pathol, Boston, MA 02115 USA

[38] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[39] German Canc Consortium DKTK, Heidelberg, Germany

[40] Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany

[41] Natl Hosp Neurol & Neurosurg, UCL Inst Neurol, Div Neuropathol, London, England

[42] UCL Inst Neurol, Dept Clin & Movement Neurosci, London, England

[43] UCL Inst Neurol, Dept Neurodegenerat Dis, London, England

[44] St Jude Childrens Res Hosp, Dept Pathol, 332 N Lauderdale St, Memphis, TN 38105 USA

[45] UCL Great Ormond St Inst Child Hlth, Dev Biol & Canc Sect, London, England

[46] Hosp Pedro Hispano, Dept Pathol, Matosinhos, Portugal

[47] Univ Amsterdam, Dept Neuro Pathol, Amsterdam UMC, Amsterdam & Stichting Epilepsie Instellingen Nede, Heemstede, Netherlands

[48] German Canc Res Ctr, Pediat Glioma Res Grp, Heidelberg, Germany

[49] Charite Univ Med Berlin, Dept Neuropathol, Berlin, Germany

[50] Free Univ Berlin, Berlin, Germany

来源：

ACTA NEUROPATHOLOGICA | 2020年 / 139卷 / 01期

基金：

英国医学研究理事会;

关键词：

Glioma; Isomorphic diffuse glioma; Epilepsy; MYB; MYBL1; Gene fusion; METHYLATION-BASED CLASSIFICATION; C-MYB; GENOMIC ANALYSIS; IDH2; MUTATIONS; DIFFERENTIATION; ASTROCYTOMAS; LANDSCAPE; TRANSFORMATION; REARRANGEMENTS; FREQUENCY;

D O I：

10.1007/s00401-019-02078-w

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

The "isomorphic subtype of diffuse astrocytoma" was identified histologically in 2004 as a supratentorial, highly differentiated glioma with low cellularity, low proliferation and focal diffuse brain infiltration. Patients typically had seizures since childhood and all were operated on as adults. To define the position of these lesions among brain tumours, we histologically, molecularly and clinically analysed 26 histologically prototypical isomorphic diffuse gliomas. Immunohistochemically, they were GFAP-positive, MAP2-, OLIG2- and CD34-negative, nuclear ATRX-expression was retained and proliferation was low. All 24 cases sequenced were IDH-wildtype. In cluster analyses of DNA methylation data, isomorphic diffuse gliomas formed a group clearly distinct from other glial/glio-neuronal brain tumours and normal hemispheric tissue, most closely related to paediatric MYB/MYBL1-altered diffuse astrocytomas and angiocentric gliomas. Half of the isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB (13/25, 52%). Gene fusions of MYBL1 or MYB with various gene partners were identified in 11/22 (50%) and were associated with an increased RNA-expression of the respective MYB-family gene. Integrating copy number alterations and available RNA sequencing data, 20/26 (77%) of isomorphic diffuse gliomas demonstrated MYBL1 (54%) or MYB (23%) alterations. Clinically, 89% of patients were seizure-free after surgery and all had a good outcome. In summary, we here define a distinct benign tumour class belonging to the family of MYB/MYBL1-altered gliomas. Isomorphic diffuse glioma occurs both in children and adults, has a concise morphology, frequent MYBL1 and MYB alterations and a specific DNA methylation profile. As an exclusively histological diagnosis may be very challenging and as paediatric MYB/MYBL1-altered diffuse astrocytomas may have the same gene fusions, we consider DNA methylation profiling very helpful for their identification.

引用

页码：193 / 209

页数：17

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