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 - Funding Information:
We thank K. B?hmer, A. Habel, S. Kocher, U. Lass, K. Lindenberg, R. Quan, S. Sprengart, U. Vogel, M. Werner and V. Zeller for excellent technical assistance. We thank the Genomics and Proteomics Core Facility of the German Cancer Research Center (DKFZ) for the performance of DNA methylation analyses. A.K. Wefers is a fellow of the Physician Scientist-Program of the Medical Faculty of Heidelberg. This study was supported by an International League against Epilepsy (ILAE) Grant to D. Capper. I. Blumcke was supported by the European Union (FP6 DESIRE Grant Agreement #602531). M. Mittelbronn would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). K. Ligon is funded by the Paediatric Low Grade Astrocytoma Foundation and NCI R01CA215489. T. Jacques is funded by The Brain Tumour Charity, Children with Cancer UK, Great Ormond Street Hospital Children?s Charity, Cancer Research UK, the Olivia Hodson Cancer Fund and the National Institute of Health Research. T. Jacques?s work is partly funded by the NIHR GOSH BRC. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. We thank the biomedical scientists in the Division of Neuropathology, the National Hospital for Neurology and Neurosurgery (NHNN) for excellent technical assistance. We also thank clinicians and neuropathologists for referring cases for molecular analysis. Part of the study was funded by the National Institute for Health Research to UCLH Biomedical research centre (BRC399/NS/RB/101410). S. Brandner and Z. Jaunmuktane are also supported by the Department of Health?s NIHR Biomedical Research Centre?s funding scheme. Additional funding was provided by the Brain Tumour Charity (UK) for the Everest Centre for Paediatric Low-Grade Brain Tumour Research.
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 -