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. 2024 Oct 18;148(1):54.
doi: 10.1007/s00401-024-02803-0.

MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes

Hye-Jung Chung  1 , Sharika Rajan  1 , Zhichao Wu  1 , Christina K Ferrone  1 , Mark Raffeld  1 , Ina Lee  1 , Jeffrey Gagan  1 , Christopher Dampier  1 , Zied Abdullaev  1 , Manoj Tyagi  1 , Patrick J Cimino  2 , Martha Quezado  1 , Kenneth Aldape  3
Affiliations

MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes

Hye-Jung Chung et al. Acta Neuropathol. .

Abstract

Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection.

Keywords: MYB; MYBL1; Glioma.

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Conflict of interest statement

All authors have no competing interests to declare.

Ethics approval was received in the form of IRB approval with a waiver of informed consent from the National Institutes of Health. The authors declare that there are no conflicts of interest. The content of the manuscript has not been published or submitted for publication elsewhere.

Figures

Fig. 1
Fig. 1
Histopathology of MYB(L1)-altered gliomas. Top: 2 cases of Angiocentric glioma (a Case 1; b Case 7), matching to methylation classes, LGG_MYB_D and LGG_MYB_B, respectively. Bottom: 2 cases of Diffuse astrocytoma, MYB- or MYBL1-altered (c Case 4; d Case 11), matching to methylation classes, LGG_MYB_C and LGG_MYB_D, respectively
Fig. 2
Fig. 2
Tail-to-tail non-productive fusions in MYB/MYBL1-altered gliomas. Direction of each coding transcript is marked under the fusion diagram generated by Arriba. a MYB::QKI tail-to-tail rearrangement in Case 5. b MYB::MMP16 (identified as MMP16::MYB) tail-to-tail rearrangement in Case 6
Fig. 3
Fig. 3
RNA sequencing coverage tracks of the MYB exons 7–15 region. Case 9 shows a reduction in read counts following exon 10, supporting a MYB rearrangement downstream of exon 10; Case 3 with a demonstrated in-frame MYB fusion at exon 9, shows a reduction in read counts following exon 9, representing a rearrangement downstream of exon 9; Case 7 with MYB truncation at exon 15, shows MYB read counts persistent up to exon 15
Fig. 4
Fig. 4
Expression levels of MYB, MYBL1 and QKI for each case in the cohort. Samples are sorted according to the type of fusion/rearrangement, and for comparison, the expression levels of 1005 pan-CNS tumor cases in the NCI clinical sequencing archives are also shown. The median level of each gene in each sample group is displayed as a line. TPM: transcripts per kilobase million
See this image and copyright information in PMC

References

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