CNS5:Diffuse astrocytoma, MYB- or MYBL1-altered

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Primary Author(s)*

Scott C. Smith, PhD, FACMG; SUNY Upstate Medical University

Cancer Category/Type

WHO Classification of Tumours of the Central Nervous System (5th Edition)

Cancer Sub-Classification / Subtype

Diffuse Astrocytoma, MYB- or MYBL1-Altered

Definition / Description of Disease

Diffuse astrocytoma, MYB or MYBL1-altered is one of several newly recognized tumor types in the 5th edition of the WHO Classification of Tumors of the Central Nervous System. The newly recognized classifications were in response to advances in understanding of paediatric-type gliomas, facilitated by an increased molecular characterisation of these tumours. Diffuse astrocytoma, MYB or MYBL1-altered is a subset of diffuse low-grade glioma with amplifications, structural variants, and fusions involving the MYB and MYBL1 protooncogenes. Diffuse astrocytoma, MYB or MYBL1-altered subtypes are without characteristic histological features of angiocentric glioma[1][2]. A related group of diffuse gliomas, the isomorphic glioma, occur predominantly in adults and are typically well-differentiated, low to moderately cellular, comprised of astrocytes with rounded nuclei and regular chromatin structures, and have low proliferative indices[3][4]. These adult diffuse gliomas exhibit alterations of MYBL1 rather than MYB . Gene fusions with multiple partners characterize the pediatric MYB or MYBL1-altered gliomas[5][6]. The most frequently identified fusion is with QKI[7][8]. The MYB or MYBL1-altered diffuse gliomas in both children and adults are generally indolent and behave in a WHO grade 1 fashion.

Clinical Features

Medically refractory epilepsy since childhood.

Signs and Symptoms History of epilepsy or seizure

Magnetic resonance imaging (MRI): well-delineated, occasionally infiltrative-appearing, non-enhancing T1-hypointense, T2-fluid attenuated inversion recovery-hyperintense lesion without restricted diffusion[9]

Laboratory Findings Genetics: Negative for IDH1 p.R132H, BRAF p.V600E; positive for MYBL1 or MYB rearrangement, amplification, or copy number change

Sites of Involvement

Supratentorial (adult), cortical and subcortical regions of the cerebral cortex (pediatric)[10]

Morphologic Features

Histomorphology: minimally to moderately hypercellular tumor; diffuse infiltration by monomorphic cells with ovoid to elongated nuclei, scant cytoplasm, fibrillary background[11][12]

Immunophenotype

Positivity for GFAP, below 1% Ki-67 index, negative for OLIG2 and IDH1 R132H[13]

Finding Marker
Positive (universal) GFAPScott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

Positive (subset) Ki-67 index below 1%
Negative (universal) OLIG2, IDH1 R132H

Chromosomal Rearrangements (Gene Fusions)

MYB or MYBL1 rearrangement

MYB or MYBL1 amplification

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
6q23.3 rearrangement Yes Yes Multiple potential  partners
8q13.1 rearrangement Yes Yes Multiple potential  partners
del(6)(q23.3q26); t(6;6)(q23.3;q26) MYB::QKI Yes Yes Creates fusion oncogenic protein

Individual Region Genomic Gain/Loss/LOH

MYB or MYBL1 copy number variation as identified by chromosomal microarray or FISH

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
6 Amp/Loss/Gain 135502446-135540310 [GRCh37] 6q23.3 Yes Yes Yes[14] [15][16][17]
8 Amp/Loss/Gain 67474410-67525453 [GRCh37] 8q13.1 Yes Yes Unknown [18][19]

Characteristic Chromosomal Patterns

Possible detection of double minutes or homogeneously stained regions by G-banding for amplification; will require confirmation of being associated with MYB or MYBL (likely by chromosomal microarray)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
6q23.3 hsr;  MYB amplification Scott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

No Unknown Unknown
8q13.1 hsr; MYBL1 amplificationScott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

No Unknown Unknown

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
MYB/MYBL1 3’-deletion MYB/MYBL1 protooncogene Deregulation of MYB/MYBL1
MYB/MYBL1 amplification MYB/MYBL1 protooncogene Overexpression of MYB/MYBL1

Genetic Diagnostic Testing Methods

Sequencing, PCR, RT-PCR, chromosomal microarray, FISH, possibly detection of double minutes or homogenously stained regions by G-banding

References

  1. ↑ Slegers, Rutger Juriaan; et al. (2020-03-09). "Low-grade developmental and epilepsy associated brain tumors: a critical update 2020". Acta Neuropathologica Communications. 8 (1): 27. doi:10.1186/s40478-020-00904-x. ISSN 2051-5960. PMC 7063704 Check |pmc= value (help). PMID 32151273 Check |pmid= value (help).
  2. ↑ Bandopadhayay, Pratiti; et al. (2016-03). "MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism". Nature Genetics. 48 (3): 273–282. doi:10.1038/ng.3500. ISSN 1546-1718. PMC 4767685. PMID 26829751. Check date values in: |date= (help)
  3. ↑ Wefers, Annika K.; et al. (2020-01). "Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course". Acta Neuropathologica. 139 (1): 193–209. doi:10.1007/s00401-019-02078-w. ISSN 1432-0533. PMC 7477753 Check |pmc= value (help). PMID 31563982. Check date values in: |date= (help)
  4. ↑ Chiang, Jason; et al. (2019-12). "A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration". Acta Neuropathologica. 138 (6): 1091–1092. doi:10.1007/s00401-019-02081-1. ISSN 1432-0533. PMC 7467132 Check |pmc= value (help). PMID 31595312. Check date values in: |date= (help)
  5. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  6. ↑ Barinfeld, Orit; et al. (2022). "Genetic Alteration Analysis of IDH1, IDH2, CDKN2A, MYB and MYBL1 in Pediatric Low-Grade Gliomas". Frontiers in Surgery. 9: 880048. doi:10.3389/fsurg.2022.880048. ISSN 2296-875X. PMC 9096721 Check |pmc= value (help). PMID 35574540 Check |pmid= value (help).
  7. ↑ Suh, Ye Yoon; et al. (2023-02-21). "MYB/MYBL1::QKI fusion-positive diffuse glioma". Journal of Neuropathology and Experimental Neurology. 82 (3): 250–260. doi:10.1093/jnen/nlac123. ISSN 1554-6578. PMC 9941827 Check |pmc= value (help). PMID 36592415 Check |pmid= value (help).
  8. ↑ Jain, Payal; et al. (2017-03-04). "MYB-QKI drives childhood brain tumors via tripartite mechanism". Cell Cycle (Georgetown, Tex.). 16 (5): 390–391. doi:10.1080/15384101.2016.1260990. ISSN 1551-4005. PMC 5351923. PMID 27973981.
  9. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  10. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  11. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  12. ↑ Suh, Ye Yoon; et al. (2023-02-21). "MYB/MYBL1::QKI fusion-positive diffuse glioma". Journal of Neuropathology and Experimental Neurology. 82 (3): 250–260. doi:10.1093/jnen/nlac123. ISSN 1554-6578. PMC 9941827 Check |pmc= value (help). PMID 36592415 Check |pmid= value (help).
  13. ↑ Wefers, Annika K.; et al. (2020-01). "Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course". Acta Neuropathologica. 139 (1): 193–209. doi:10.1007/s00401-019-02078-w. ISSN 1432-0533. PMC 7477753 Check |pmc= value (help). PMID 31563982. Check date values in: |date= (help)
  14. ↑ Trkova, Katerina; et al. (2023-09). "DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy". Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 39 (9): 2509–2513. doi:10.1007/s00381-023-05976-3. ISSN 1433-0350. PMC PMC10432314 Check |pmc= value (help). PMID 37165121 Check |pmid= value (help). Check date values in: |date= (help)CS1 maint: PMC format (link)
  15. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  16. ↑ Bale, Tejus A.; et al. (2022-07). "The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors". Brain Pathology (Zurich, Switzerland). 32 (4): e13060. doi:10.1111/bpa.13060. ISSN 1750-3639. PMC 9245930 Check |pmc= value (help). PMID 35218102 Check |pmid= value (help). Check date values in: |date= (help)
  17. ↑ Trkova, Katerina; et al. (2023-09). "DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy". Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 39 (9): 2509–2513. doi:10.1007/s00381-023-05976-3. ISSN 1433-0350. PMC PMC10432314 Check |pmc= value (help). PMID 37165121 Check |pmid= value (help). Check date values in: |date= (help)CS1 maint: PMC format (link)
  18. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  19. ↑ Bale, Tejus A.; et al. (2022-07). "The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors". Brain Pathology (Zurich, Switzerland). 32 (4): e13060. doi:10.1111/bpa.13060. ISSN 1750-3639. PMC 9245930 Check |pmc= value (help). PMID 35218102 Check |pmid= value (help). Check date values in: |date= (help)

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