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

TY - JOUR

T1 - Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course

AU - Wefers, Annika K

AU - Stichel, Damian

AU - Schrimpf, Daniel

AU - Coras, Roland

AU - Pages, Mélanie

AU - Tauziède-Espariat, Arnault

AU - Varlet, Pascale

AU - Schwarz, Daniel

AU - Söylemezoglu, Figen

AU - Pohl, Ute

AU - Pimentel, José

AU - Meyer, Jochen

AU - Hewer, Ekkehard

AU - Japp, Anna

AU - Joshi, Abhijit

AU - Reuss, David E

AU - Reinhardt, Annekathrin

AU - Sievers, Philipp

AU - Casalini, M Belén

AU - Ebrahimi, Azadeh

AU - Huang, Kristin

AU - Koelsche, Christian

AU - Low, Hu Liang

AU - Rebelo, Olinda

AU - Marnoto, Dina

AU - Becker, Albert J

AU - Staszewski, Ori

AU - Mittelbronn, Michel

AU - Hasselblatt, Martin

AU - Schittenhelm, Jens

AU - Cheesman, Edmund

AU - de Oliveira, Ricardo Santos

AU - Queiroz, Rosane Gomes P

AU - Valera, Elvis Terci

AU - Hans, Volkmar H

AU - Korshunov, Andrey

AU - Olar, Adriana

AU - Ligon, Keith L

AU - Pfister, Stefan M

AU - Jaunmuktane, Zane

AU - Brandner, Sebastian

AU - Tatevossian, Ruth G

AU - Ellison, David W

AU - Jacques, Thomas S

AU - Honavar, Mrinalini

AU - Aronica, Eleonora

AU - Thom, Maria

AU - Sahm, Felix

AU - von Deimling, Andreas

AU - Jones, David T W

AU - Blumcke, Ingmar

AU - Capper, David

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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.

KW - Adult

KW - Brain Neoplasms/genetics

KW - Child

KW - Child, Preschool

KW - DNA Copy Number Variations

KW - DNA Methylation

KW - Female

KW - Glioma/genetics

KW - Humans

KW - Male

KW - Middle Aged

KW - Oncogene Fusion

KW - Proto-Oncogene Proteins/genetics

KW - Proto-Oncogene Proteins c-myb/genetics

KW - Trans-Activators/genetics

KW - Young Adult

U2 - 10.1007/s00401-019-02078-w

DO - 10.1007/s00401-019-02078-w

M3 - SCORING: Journal article

C2 - 31563982

VL - 139

SP - 193

EP - 209

JO - ACTA NEUROPATHOL

JF - ACTA NEUROPATHOL

SN - 0001-6322

IS - 1

ER -