Abstract A045: The functional role of UBASH3B in HPV-head and neck squamous cell carcinoma and implications on racial disparities

Abstract Head and Neck Squamous Cell Carcinoma (HNSCC) is a group of malignancies that develop from the epithelial lining of the oral cavity, pharynx, and larynx. Notably, HNSCC is one of the top cancers with pronounced racial disparities in clinical outcomes, where African Americans (AAs) exhibit significantly poorer overall survival compared to European Americans (EAs). This disparity is observed more in the HPV negative (HPV-) HNSCC subtype. Although this disparity is multifactorial, recent studies suggest biological factors may also contribute to this disparity. The epidermal growth factor receptor (EGFR), an important player in HPV- HNSCC, whose activity leads to cancer progression. Previous work has identified UBASH3B, a protein tyrosine phosphatase that stabilizes EGFR, as an emerging key player in tumorigenesis. In the current study, we explored the role of UBASH3B in HPV- HNSCC though an integrated analysis of The Cancer Genome Atlas (TCGA, n=378) and functional in vitro assays. Transcriptomic data revealed significant upregulation of UBASH3B in HPV- HNSCC. Race stratified survival analysis showed that high expression of UBASH3B expression was significantly associated with worse overall survival in AAs, but not in EAs. Copy number values of UBASH3B in HPV- HNSCC patients showed a significant positive correlation with UBASH3B expression. Functional knockdown of UBASH3B in HPV- HNSCC cell lines led to significant reduction in cell viability and migration. Additionally, UBASH3B knockdown correlated with the downregulation of key oncogenic pathways, including the EGFR-AKT pathway, EMT, and cell cycle regulation. Gene set enrichment analysis (GSEA) revealed significant enrichment in pathways involving cell signaling, and cell proliferation for AA patients with high UBASH3B expression. Moreover, UBASH3B expression positively correlated with infiltration of CD4+ T cells and M1 macrophages. These findings identify UBASH3B as a potential oncogenic driver in HPV- HNSCC supported by its overexpression and role in promoting cell proliferation and migration. Additionally, survival analysis and GSEA further reveal that AAs patients most impacted by UBASH3B’s role in tumorigenesis, reflected by its association with worse overall survival and upregulation of multiple oncogenic pathways exclusively in this group. These results suggest UBASH3B may contribute to racial disparities in clinical outcomes by modulating distinct cellular processes, highlighting UBASH3B as a promising therapeutic target for HPV-HNSCC AA patients. Citation Format: Madeleine Ndahayo, Sophie Werner, Cameron Westlake, Erin Allor, Ishita Gupta, Daria A. Gaykalova. The functional role of UBASH3B in HPV-head and neck squamous cell carcinoma and implications on racial disparities [abstract]. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr A045.