COSMIC mutational signature analysis showed that RAC1-A159V-mutated and G-box-mutated HNSCC tumors, when compared to non-mutated RAC1-wildtye (WT) tumors, carried a 2.3-fold enriched signature of SBS10b (p = 0.0128 for A159V; p = 0.043 for G-box-mutated HNSCC) associated with polymerase epsilon exonuclease domain mutations [20], and an 8.1-fold enriched signature of SBS20 (p = 0.0014 for A159V; p = 0.0284 for G-box-mutated HNSCC) associated with concurrent POLD1 mutations, defective DNA mismatch repair, and microsatellite instability (MSI). This evidence concerns the gene POLD1 and head and neck squamous cell carcinoma.