The Proteomic Landscape of Growth Factor Signaling Networks Associated with Mutations in Head and Neck Cancers.

FAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with mutations and clinical outcomes of patients with HNSCC. mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. mutation was significantly more prevalent among HPV(-), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. mutation was also significantly associated with lower gene expression and increased protein expression of HER3_pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FAT1 mutation in oral cancer co-occurred with top mutated genes and . Poorer overall survival or progression-free survival was observed in patients with mutation or altered HER3_pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHER2, and pERK and upregulated pHER3 and HER3 proteins were observed in two knockout HNSCC cell lines, supporting that alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of and gene expressions was identified. Collectively, these results suggest that alteration of appears to involve mostly HPV(-) HNSCC and may contribute to resistance to EGFR-targeted therapy. SIGNIFICANCE: Integrative bioinformatics and statistical analyses reveal a panel of genes and proteins associated with mutation in HNSCC, providing important insights into prospective clinical investigations with targeted therapies.