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

Abstract

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-and CD34-negative and nuclear ATRX expression was retained. 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. It was most closely related to paediatric MYB/MYBL1 altered diffuse astrocytomas and angiocentric gliomas. 13/25 (52%) of isomorphic diffuse gliomas had copy number alterations of MYBL1 or MYB. Gene fusions of MYBL1 or MYB with various gene partners were detected in 11/22 (50%). Gene fusions were associated with increased RNA-expression of the respective MYBfamily gene in 83%. Integrating copy number alterations and RNA sequencing data, 20/26 (77%) had either 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 tumour class with a concise morphology, a typical DNA-methylation profile and frequent MYBL1 and MYB alterations. It occurs both in children and adults and has a benign disease course. For classification, we propose the term "isomorphic diffuse glioma, MYBL1/MYB altered, WHO grade I". DNA-methylation profiling is well suited to identify these tumours.

Low-grade developmental and epilepsy associated brain tumors: a critical update 2020

“…The closest relation was found with a cluster of angiocentric glioma. Interestingly, 77% of IDGs also had alterations in the MYBL1-or MYB-loci, mostly representing copy number alterations or MYBL1-and MYB-fusions as shown by RNA sequencing [75]. Although IDG tumors were first reported in 2004 and not yet been recognized by the WHO panel, they likely represent a distinct (3rd) group of genetically defined LEAT and which association/familiarity with AG is in need of further clarification (Fig.…”

“…The term "long-term epilepsy associated tumors (LEATs)" was introduced by Luyken and coworker from the Bonn epilepsy center in 2003 to also recognize rare tumor entities in patients with drug-resistant long-term epilepsy that do not match with the WHO description and nosology, but are likely more close to the GG and DNT spectrum [44]. Further examples for this hitherto ongoing discovery of LEAT entities are papillary glio-neuronal tumor described in 1998 [42], angiocentric gliomas described in 2005 [73], isomorphic astrocytoma described in 2004 [6] and now referred to as isomorphic diffuse glioma [75], multinodular and vacuolating neuronal tumors of the cerebrum in 2014 [10], and polymorphous low-grade neuroepithelial tumor of the young in 2017 [34].…”

Invited Review: DNA methylation‐based classification of paediatric brain tumours

“…A graphical summary of the evolution of the field within the context of brain tumours is displayed in Figure . DNA methylation is further gaining importance for tumour entity definition and is increasingly being used for the allocation of rare cancers into either known tumour classes or the identification of new entities , a collection of which are summarized in Figure .…”

“…Signs of histological malignancy are not observed and these lesions may rather contrarily be mistakenly classified as normal or reactive brain tissue. The majority of cases display chromosomal alterations in either MYBL1 or MYB and the tumours have a distinct DNA methylation profile .…”

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…have become mandatory for a conclusive diagnosis of many specific tumor entities [6][7][8][9]. Moreover, in the following few years since its publication, the diagnostic/prognostic/predictive importance of many additional molecular traits have been demonstrated and they are now being quickly translated into the routine clinical practice [10][11][12].…”