The Proteomic Landscape Of Growth Factor Signaling Networks Associated With Fat1 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 FATI mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with FATI mutations and clinical outcomes of patients with HNSCC. FATI mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. FATI mutation was significantly more prevalent among HPV(-), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. FATI mutation was also significantly associated with lower FATI gene expression and increased protein expression of HER3_pY1289, IRS1, and CAVEOLIN1. From an independent International Cancer Genome Consortium dataset, FATI mutation in oral cancer cooccurred with top mutated genes TP53 and CASP8. Poorer overall survival or progression-free survival was observed in patients with FATI mutation or altered HER3 pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to FAT! mutations in HNSCC, and protein signature panels uncovered the heterogeneity of patient subgroups. Decreased pEGFR, pHEI22, and pERK and upregulated pHER3 and HER3 proteins were observed in two FATI knockout HNSCC cell lines, supporting that FATI alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of FATI and EGFR gene expressions was identified. Collectively, these results suggest that alteration of FATI 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 FATI mutation in HNSCC, providing important insights into prospective clinical investigations with targeted therapies.