The Proteomic Landscape of Growth Factor Signaling Networks Associated with <i>FAT1</i> Mutations in Head and Neck Cancers.

Abstract

FAT1 is frequently mutated in head and neck squamous cell carcinoma (HNSCC), but the biological and clinical effects of <i>FAT1</i> mutations in HNSCC remain to be fully elucidated. We investigated the landscape of altered protein and gene expression associated with <i>FAT1</i> mutations and clinical outcomes of patients with HNSCC. <i>FAT1</i> mutation was stratified with clinical information from The Cancer Genome Atlas HNSCC databases with more than 200 proteins or phosphorylated sites. <i>FAT1</i> mutation was significantly more prevalent among HPV(-), female, and older patients and was enriched in oral, larynx, and hypopharynx primary tumors. <i>FAT1</i> mutation was also significantly associated with lower <i>FAT1</i> 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 <i>TP53</i> and <i>CASP8</i>. Poorer overall survival or progression-free survival was observed in patients with <i>FAT1</i> mutation or altered HER3_pY1289, IRS1, or CAVEOLIN1. Pathway analysis revealed dominant ERBB/neuregulin pathways linked to <i>FAT1</i> 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 <i>FAT1</i> knockout HNSCC cell lines, supporting that <i>FAT1</i> alterations lead to altered EGFR/ERBB signaling. In squamous cancers of the lung and cervix, a strong association of <i>FAT1</i> and <i>EGFR</i> gene expressions was identified. Collectively, these results suggest that alteration of <i>FAT1</i> 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 <i>FAT1</i> mutation in HNSCC, providing important insights into prospective clinical investigations with targeted therapies.