Comprehensive genomic analyses have been performed for head and neck squamous cell carcinoma (HNSCC), revealing a significant rate of NOTCH1 mutations and identifying NOTCH1 as the second most frequently mutated gene after TP53. Most NOTCH1 mutations are considered inactivating, indicating that NOTCH1 is a tumor suppressor gene. On the other hand, cohorts from Asian populations with HNSCC have shown activating NOTCH1 mutations. HNSCC with NOTCH1 mutations have a worse prognosis than the NOTCH1 wild-type tumors. Additional data on other NOTCH family members have shown that NOTCH promotes HNSCC progression. NOTCH family members, including NOTCH pathway genes, are upregulated in HNSCC compared with normal tissues, and inhibition of the NOTCH pathway decreases cell proliferation and invasion. NOTCH activity in HNSCC is therefore contextual, and NOTCH in HNSCC is considered to have a bimodal role as a tumor suppressor and an oncogene. In this review, recent understandings of NOTCH pathway genes, including NOTCH genes, in HNSCC are described. In addition, the implications of NOTCH pathway alteration for HNSCC-specific NOTCH-targeted cancer therapy are explored.
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