Comprehensive analysis of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma

Abstract

Background: Pediatric-type diffuse low-grade gliomas (pLGG) harboring recurrent genetic alterations involving MYB or MYBL1 are closely related tumors. Detailed treatment and outcome data of large cohorts are still limited. This study aimed to comprehensively evaluate pLGG with these alterations to define optimal therapeutic strategies.

Methods: We retrospectively reviewed details of pLGG with MYB or MYBL1 alterations from patients treated or referred for pathologic review at St. Jude Children's Research Hospital. Tumor specimens were centrally reviewed, and clinical data were collated.

Results: Thirty-three patients (18 male; median age, 5 years) were identified. Two tumors had MYBL1 alterations; 31 had MYB alterations, MYB::QKI fusion being the most common (n = 10, 30%). Most tumors were in the cerebral hemispheres (n = 22, 67%). Two patients (6%) had metastasis at diagnosis. The median follow-up was 6.1 years. The 5-year event-free survival (EFS) rate was 81.3% ± 8.3%; the 5-year overall survival (OS) rate was 96.4% ± 4.1%. Patients receiving a near-total or gross-total resection had a 5-year EFS of 100%; those receiving a biopsy or subtotal resection had a 5-year EFS rate of 56.6% ± 15.2% (P < .01). No difference in EFS was observed based on location, histology, or molecular alterations. However, the tumors that progressed or metastasized may have distinct methylation profiles with evidence of activation of the MAPK and PI3K/AKT/mTOR pathways.

Conclusions: pLGG with MYB/MYBL1 alterations have good outcomes. Our findings suggest that surgical resectability is a crucial determinant of EFS. Further characterization is required to identify optimal treatment strategies for progressive tumors.

Keywords: MYB/MYBL1 alterations; outcome; pediatric diffuse low-grade glioma; survival; treatment.

Figure 1.

Genetic alteration and clinical characteristics among 33 MYB/MYBL1-altered pediatric-type diffuse low-grade glioma. Samples are arranged in columns, with categories labeled along the rows.

Figure 2.

Histopathology of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma. (A) Tumors with the angiocentric glioma pattern showed apparent angiocentric growth with areas resembling diffuse astrocytoma. Entrapped neurons could be seen. (B) Tumors with the diffuse astrocytoma pattern frequently showed variable degrees of angiocentric growth around small vessels. (C) Isomorphic diffuse glioma showed subtle changes in cellularity. (D) The tumors demonstrated extensive infiltration of the involved CNS parenchyma with numerous entrapped neurofilament-positive axons. (E) The tumor cells were positive for GFAP. (F, G) Tumor cells showing angiocentric growth were negative for Olig2 and Sox10. (H) MAP2 immunoreactivity was observed in the angiocentric tumor cells. (I) Perinuclear dot-like EMA immunoreactivity was a characteristic finding. Scale bar: 100 μm.

Figure 3.

DNA methylation–based characterization of MYB/MYBL1-altered pediatric-type diffuse low-grade glioma. (A) t-SNE plot of the cohort. (B) Unsupervised hierarchical clustering. (C) Metastasized and progressive MYB-altered tumors showed increased immunoreactivity for phospho-ERK1/2 (pERK1/2), a marker of activated MAPK pathway. (D) Metastasized and progressive MYB-altered tumors showed increased immunoreactivity for phospho-S6 (pS6), a marker of activated PI3K/AKT/mTOR pathway. ATRT: atypical teratoid rhabdoid tumor; BCOR: CNS tumor with BCOR internal tandem duplication; CBPA: cerebellar pilocytic astrocytoma; CIC: CIC-fused sarcoma; DNET: dysembryoplastic neuroepithelial tumor; ETMR: embryonal tumor with multilayered rosettes; FOXR2: FOXR2-activated CNS neuroblastoma; G3/G4: group 3/group 4 medulloblastoma; G34: H3 G34-altered diffuse hemispheric glioma; HTPA: hypothalamic pilocytic astrocytoma; IDH-A/O: IDH-mutant astrocytoma and oligodendroglioma; IHG: infant-type hemispheric glioma; K27: H3 K27-altered diffuse midline glioma; MGNT: myxoid glioneuronal tumor; MN1: MN1-altered astroblastoma; MYB-M: MYB-altered tumors with metastasis; MYB-P: progressive MYB-altered tumors; PB: pineoblastoma; RGNT: rosette-forming glioneuronal tumor; SEGA: subependymal giant cell astrocytoma; SHH-CHL/AD: childhood/adult SHH-activated medulloblastoma; WNT-WNT-activated medulloblastoma; YAP: YAP1-fused ependymoma; ZFTA: ZFTA-fused ependymoma. Scale bar: 100 μm.

Figure 4.

Swimmer plot of patients with biopsy or STR. Bars for each patient are colored based on the initial surgical procedure. Events and interventions are described in the figure legend.

Figure 5.

Kaplan–Meier plots of cohort outcomes. (A) Overall survival of the whole cohort. (B) Event-free survival of the whole cohort. (C) Event-free survival based on the degree of surgical resection. (D) Event-free survival separated by anatomic location. (E) Event-free survival separated by histology. (F) Event-free survival based on molecular alterations. P-value calculated by the log-rank test.