We concluded that TGFBR1 alterations in CAL27 impairs TGF-β signaling, while in the absence of other detectable abnormalities in the pathway, the SMAD4 H132Y mutation present in UM-SCC-2 likely behaves as a dominant negative protein, effectively preventing SMAD2/3-mediated transcription in this HNSCC line. This evidence concerns the gene SMAD2 and head and neck squamous cell carcinoma.