Abstract Background: Black patients with head and neck squamous cell carcinoma (HNSCC) have maintained poor survival outcomes. This disparity has persisted despite controlling for sociodemographic factors. The overall goal of this study was to identify genomic regulators and pathways that may underlie differences in survival outcomes using data from TCGA and cell lines. Methods: The Cancer Genome Atlas (TCGA) HNSCC cohort gene expression data from 44 Black and 438 White patients was downloaded from UCSC Xena. Only HPV-negative subsites were included. Cell line data from 4 HNSCC cell lines (African ancestry=2, European ancestry=2) was generated using RNA sequencing and tandem mass spectrometry. EdgeR identified differentially expressed genes in HNSCC TCGA cohort and cell lines (FDR 0.05, -1 log((FC)) 1). KEGG pathway analysis was performed to identify pathway enrichment for TCGA cohort and cell lines via clusterProfiler in R studio (p.adj 0.05). Kaplan-Meier survival analyses with log-ranked tests were conducted using survival/survminer R packages to assess overall survival associated with gene expression (log-rank test, p0.05). miRDB was used to predict miRNAs that regulate genes associated with overall survival. Results: KEGG pathway analysis revealed that genes with higher expression in Black HNSCC were enriched for drug metabolic pathways, including platinum drug resistance (p adj.= 1.86x10-4) and drug metabolism by cytochrome p450 (p adj.= 2.24x10-8). Lower expressed genes were enriched for cardiomyopathic pathways, such as hypertrophic cardiomyopathy (p adj.= 3.30x10-6) and dilated cardiomyopathy (p adj.= 4.84x10-6). Similarly, in HNSCC cell lines of African ancestry, genes and proteins with higher expression were enriched for glutathione metabolism (p adj.= 4.44x10-2). Lower expressed were enriched for actin cytoskeletal function (p adj.= 5.05x10-3). Survival analysis revealed that high expression of glutathione metabolism genes GSR, MGST1, GCLC, and G6PD were significantly associated with poor overall survival in Black patients (p0.05). Low expression of actin cytoskeletal genes MYH11, PAK4, PARVA, and ITGB2 were also significantly associated with poor overall survival in Black patients (p0.01). Building upon this survival analysis, we identified that 9 miRNAs regulate the glutathione genes, and 7 miRNAs regulate the actin cytoskeletal genes. Six of these miRNAs, miR-9-5p, miR-7-5p, miR-200c-3p, miR-138-5p, miR-99a-5p, and miR-145-5p share overlapping pathways as they regulate both the glutathione and actin cytoskeletal genes. Conclusion: We propose a genomic signature in which a cluster of miRNAs are associated with drug resistance and actin cytoskeletal pathways that may predict poor overall survival in Black HNSCC patients. Future directions will involve characterizing these miRNAs and mechanisms of regulation in TCGA and HNSCC cell lines. C.L. and C.W. contributed equally to this work Citation Format: Chayil C. Lattimore, Caretia J. Washington, Dejana Braithwaite, Shama D. Karanth, Kristianna M. Fredenburg. Unlocking a potential genomic signature associated with disparate head and neck squamous cell carcinoma (HNSCC) outcomes 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 A036.
Lattimore et al. (Thu,) studied this question.