Pediatric-type Diffuse Low-grade Gliomas

2023-07-26   Scott Ryall, PhD 

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

The 2021 WHO guidelines for CNS tumor classification recognizes two new families of tumor types that acknowledge the key diagnostic differences between pediatric-type gliomas and other diffuse gliomas: i) pediatric-type diffuse low-grade gliomas and ii) pediatric-type diffuse high-grade gliomas. 1 Pediatric-type diffuse low-grade gliomas include 4 entities unified by diffuse growth and (sometimes) overlapping histological features. The precise classification of these tumors requires an integrated diagnostic approach in which histopathological and molecular features are considered. 2 These 4 entities are: i) diffuse astrocytoma, MYB- or MYBL1-altered ii) angiocentric glioma, iii) polymorphous low-grade neuroepithelial tumor of the young (PLNTY), and iv) diffuse low-grade glioma, MAPK pathway-altered. 

Paediatric-type Diffuse Low-grade GliomasGenetic Event(s)
Diffuse astrocytoma, MYB- or MYBL1-alteredDiffuse astrocytoma, MYB- or MYBL1-altered are defined by structural variants that result in a fusion between MYB or MYBL1 and various partner genes which include PCDHGA1, MMP16, and MAML2. 3-7 MYB::QKI is rarely seen in these tumors, but rather, in angiocentric glioma 7,8. These tumors do not harbor mutations in IDH1, IDH2, TP53, ATRX, or histone H3 genes. 7,9
Angiocentric gliomaAngiocentric glioma are define by rearrangements and/or copy-number alterations involving MYB. 4,10,11 Mostly commonly, these are MYB::QKI fusions, which account for >85% of tumors 4,7,8,10,12,13. Rarely, MYB has been shown to fuse with other genes including PCDHGA1, ESR1, and MMP16 7. These tumors do not harbor mutations in IDH1, IDH2, TP53, ATRX, or histone H3 genes. 4,7,14.
Polymorphous low-grade neuroepithelial tumour of the youngPolymorphous low-grade neuroepithelial tumour of the young (PLNTY) habor MAPK pathway–activating abnormalities, most often BRAF p.V600E 15-19 or FGFR2/FGFR3 fusions 15,17,19-21. These fusions include FGFR2::CTNNA3, FGFR2::SHTN1, FGFR2::INA, and FGFR3::TACC3, the former of which appears in be exclusively observed in PLNTY. 9,22 These tumors do not harbor mutations in IDH1, IDH2, TP53, ATRX, or histone H3 genes and do not exhibit 1p/19q codeletion. Methylation analysis shows PLNTY as a distinct entity that is most similar to ganglioglioma. 15
Diffuse low-grade glioma, MAPK pathway-alteredDiffuse low-grade glioma, MAPK pathway-altered harbor MAPK pathway alterations in the absence of mutations in IDH1, IDH2, TP53, ATRX, or histone H3 gene and without homozygous deletions of CDKN2A. The most common MAPK alterations include BRAF p.V600E or FGFR1 alterations including a tyrosine kinase domain (TKD) duplications, mutations or fusions. 3,4,9. Less common alterations include those involving FGFR2, NTRK1/NTRK2/NTRK3, MAP2K1, and MET, which are also thought to result in MAPK pathway activation. 9 DNA methylation analysis does not separate these tumors into a single entity, but rather, they cluster with other tumor types that have shared genetic alterations 4,23.

Article Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
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3235839812013Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas.Zhang J et al
4268100702016Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology.Qaddoumi I et al
5308483472019cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAF(V600E) mutation.Ellison DW et al
6315639822020Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course.Wefers AK et al
7315953122019A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration.Chiang J et al
8268297512016MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.Bandopadhayay P et al
9322892782020Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.Ryall S et al
10210464102010MYB upregulation and genetic aberrations in a subset of pediatric low-grade gliomas.Tatevossian RG et al
11236335652013Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1.Ramkissoon LA et al
12287760912017Angiocentric glioma with MYB-QKI fusion located in the brainstem, rather than cerebral cortex.Chan E et al
13288033982017Brainstem angiocentric gliomas with MYB-QKI rearrangements.D'Aronco L et al
14224453622012Isocitrate dehydrogenase 1 R132H mutation is not detected in angiocentric glioma.Raghunathan A et al
15278127922017Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway.Huse JT et al
16297011692018A newly diagnosed case of polymorphous low-grade neuroepithelial tumor of the young.Bitar M et al
17313966642019Plenty of calcification: imaging characterization of polymorphous low-grade neuroepithelial tumor of the young.Johnson DR et al
18315207662019Polymorphous Low-Grade Neuroepithelial Tumor of the Young: A Case Report with Genomic Findings.Gupta VR et al
19316179142019Genomic Analysis of Dysembryoplastic Neuroepithelial Tumor Spectrum Reveals a Diversity of Molecular Alterations Dysregulating the MAPK and PI3K/mTOR Pathways.Surrey LF et al
20300515332018Low-grade neuroepithelial tumor: Unusual presentation in an adult without history of seizures.Riva G et al
21322526642020Polymorphous low-grade neuroepithelial tumor of the young: case report and review focus on the radiological features and genetic alterations.Chen Y et al
22320858052020FGFR- gene family alterations in low-grade neuroepithelial tumors.Bale TA et al
23295396392018DNA methylation-based classification of central nervous system tumours.Capper D et al

Citation

Scott Ryall, PhD

Pediatric-type Diffuse Low-grade Gliomas

Atlas Genet Cytogenet Oncol Haematol. 2023-07-26

Online version: http://atlasgeneticsoncology.org/solid-tumor/209192/pediatric-type-diffuse-low-grade-gliomas