The role of the ubiquitin ligase UBE4B in neural tumors in adults and children.
Authors: Zage Peter E. , Le Clorennec Christophe , Adeyelu Tolulope Tosin , Xiu Joanne , Aulakh Sonikpreet , Antonarakis Emmanuel S. , Ahluwalia Manmeet Singh , Nicolaides Theodore , Glantz Michael J. , Oberley Matthew James 
Published: July 2024

e14034

Background: In cancers of the nervous system such as neuroblastoma (NB), the ubiquitin ligase UBE4B directly ubiquitinates growth factor receptors (GFRs), influencing their trafficking and lysosomal degradation. While the diverse functions of UBE4B are acknowledged, we hypothesize that UBE4B expression has distinct associations with outcomes in pediatric versus adult nervous system cancers. We examined the impact of UBE4B expression on glioblastoma (GBM) development, growth, and metastasis by correlating its expression with patient outcomes across age groups. Methods: Glioblastoma samples that were IDH1/2 wild type (n = 2072) underwent DNA (592-gene/whole-exome) and RNA (whole transcriptome) sequencing at Caris Life Sciences. Samples were stratified by UBE4B expression (transcripts per million – TPM) quartiles for all GBM tumors (Q4: H and Q1: L) and by patient age at the time of tissue collection (younger: < 30 years; older: > 60 years). Cell infiltration in the tumor microenvironment was inferred by quanTIseq. Gene expression profiles were analyzed for transcriptomic signature predictive of response to immunotherapy. Overall survival (OS) was derived from insurance claims data, and Kaplan-Meier estimates were calculated. Mann-Whitney U and Chi-square/Fisher-Exact tests were applied were appropriate, with p-values adjusted for multiple comparison. Results: UBE4B expression was similar between younger (n = 57) and older (n = 1115) glioblastoma patients (median: 24.7 vs. 21.6 TPM, p = 0.17). In younger patients, those with high UBE4B expression showed improved OS compared to low expressors (24.9 vs 19.2 months [mos]; HR = 0.41, 95% CI 0.15 – 1.11, p = 0.07). However, UBE4B expression was not associated with OS among older GBM patients (13.5 vs 12.9 mos; HR 1.10 95% CI 0.9 – 1.3, p = 0.33). Within the younger cohorts, higher expression of growth factor receptor genes was observed in high compared to low UBE4B expression ( EGFR: 96.57 vs. 7.07 TPM, p = 0.0092; RET: 0.99 vs. 0.30 TPM, p = 0.018; NTRK2: 236.9 vs. 29.5 TPM, p = 0.084). Concurrent mutation of PDGFRA was also exclusively observed in UBE4B-high tumors (42.9% vs. 0% in UBE4B-L, p = 0.024). Transcriptomic analysis, however, showed that UBE4B-high tumors had lower IFN-g signature scores compared to UBE4B-L (-0.62 vs. -0.41 arbitrary units, p = 0.02). M1 macrophage cell fractions were lower in UBE4B-high compared to UBE4B-low (median: 0.33% vs. 3.38%, p = 0.005), while the fraction of B cells was significantly higher (median: 9.57% vs. 8.14%, p = 0.009). Conclusions: Higher UBE4B expression in younger GBM cases correlated with improved OS suggesting it may have utility as a prognostic biomarker. Increased expression of GFRs in younger patients with high UBE4B expression may provide rationale for new treatment strategies in these patients. Future work may prioritize designing drug targets for UBE4B, offering therapeutic opportunities, especially for younger GBM patients.