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Head and neck squamous cell carcinoma (HNSCC) exhibits significant survival disparities by ancestry. This review explores how genetic ancestry shapes the clinical and molecular features of HNSCC, providing insights into the molecular mechanisms underlying these disparities. We reveal the variation in gene expression, mutations, copy number alterations, and DNA methylation patterns between ancestral groups. These insights highlight the potential for more personalized, ancestry-informed therapies, advancing equity in cancer treatment.