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
N1 - Publisher Copyright:
© 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
PY - 2020/1/1
Y1 - 2020/1/1
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 - Epilepsy
KW - Gene fusion
KW - Glioma
KW - Isomorphic diffuse glioma
KW - MYB
KW - MYBL1
UR - http://www.scopus.com/inward/record.url?scp=85074098031&partnerID=8YFLogxK
U2 - 10.1007/s00401-019-02078-w
DO - 10.1007/s00401-019-02078-w
M3 - Article
C2 - 31563982
AN - SCOPUS:85074098031
SN - 0001-6322
VL - 139
SP - 193
EP - 209
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 1
ER -