CNS5:Diffuse astrocytoma, MYB- or MYBL1-altered

Central Nervous System Tumours(WHO Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

Primary Author(s)*

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

WHO Classification of Disease

Structure	Disease
Book	Central Nervous System Tumours (5th ed.)
Category	Gliomas, glioneuronal tumours, and neuronal tumours
Family	Gliomas, glioneuronal tumours, and neuronal tumours
Type	Paediatric-type diffuse low-grade gliomas
Subtype(s)	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 5^th 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. 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. These adult diffuse gliomas exhibit alterations of MYBL1 rather than MYB . Gene fusions with multiple partners characterize the pediatric MYB or MYBL1-altered gliomas. The most frequently identified fusion is with QKI. 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
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)

Morphologic Features

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

Immunophenotype

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

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

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

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

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

Chr #	Gain, Loss, Amp, LOH	Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]	Relevant Gene(s)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

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
8	Amp/Loss/Gain	67474410-67525453 [GRCh37]	8q13.1	Yes	Yes	Unknown

Characteristic Chromosomal or Other Global Mutational Patterns

Put your text here and fill in the table (Instructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Chromosomal Pattern	Molecular Pathogenesis	Prevalence - Common >20%, Recurrent 5-20% or Rare <5% (Disease)	Diagnostic, Prognostic, and Therapeutic Significance - D, P, T	Established Clinical Significance Per Guidelines - Yes or No (Source)	Clinical Relevance Details/Other Notes
EXAMPLE: Co-deletion of 1p and 18q	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).	EXAMPLE: Common (Oligodendroglioma)	EXAMPLE: D, P
EXAMPLE: Microsatellite instability - hypermutated		EXAMPLE: Common (Endometrial carcinoma)	EXAMPLE: P, T

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

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the Associate Editor or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.

Prior Author(s): *Citation of this Page: “Diffuse astrocytoma, MYB- or MYBL1-altered”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/27/2025, https://ccga.io/index.php/CNS5:Diffuse astrocytoma, MYB- or MYBL1-altered.