Abstract 321: Identification of proteins associated with FAT1 mutations which potentially contribute to oncogenesis and progression of head and neck cancers
Authors: Chen Zhuo Georgia , Chen Zhengjia , Zhang Chao , Chen Jianhong , Wang Dongsheng , Saba Nabil F. , Chen Zhong 
Published: July 2021

Abstract
Objectives: The Cancer Genome Atlas (TCGA) reported a FAT1 mutation rate of 23% in head and neck squamous cell carcinoma (HNSCC), which was higher in human papilloma virus (HPV)-negative cancer. Wild-type FAT1 exhibits a tumor suppressor activity, and the majority of mutated FAT1 genes are inactivated by missense or truncation, leading to altered or terminated gene products. However, the roles of FAT1 mutants in HNSCC oncogenesis and progression remain poorly understood.
Methods: We investigated the landscape of altered protein and gene expression associated with FAT1 mutation, which predicted clinical outcomes of 329 HNSCC patients. The relationships of FAT1 mutation with clinical information from HNSCC datasets of TCGA were tested using Chi-Square or Fisher's exact test. The association of FAT1 mutation with more than 200 proteins or phosphorylated sites detected by Reverse Phase Protein Arrays (RPPA) was revealed using Student's T-test. Overall survival (OS) and progression-free survival (PFS) were analyzed with Kaplan Meier method, Log-rank tests, and COX model. Hierarchical clustering classified HNSCC subgroups, and the underlying signaling pathways and regulatory networks were revealed by Ingenuity Pathway Analysis (IPA).
Results: Clinically, the prevalence of FAT1 mutation was significantly associated with HPV(-), female, or older patients, and enriched in the oral cavity and larynx/hypopharynx primary tumor sites. FAT1 mutation was significantly associated with lower FAT1 gene expression and increased protein expression of HER3_pY1289, IRS1, CAVEOLIN1 and VEGFR2, while twelve proteins were upregulated in patients with wild type FAT1, including immune check point molecule PD1. Poorer OS or PFS was observed in patients with FAT1 mutation and/or altered HER3_pY1289, IRS1, CYCLINE2, RET_pY905, P16INK4A, CMYC, MTORpS2448, or CAVEOLIN. IPA revealed dominant ERBB/neuregulin pathways, and protein signature panels divulged the heterogeneity of patient subgroups and predicted PFS. Alteration of FAT1 appears to involve mostly HPV-unrelated HNSCC and may contribute to the resistance to EGFR-targeted therapy and immunotherapy.
Summary: We revealed dozens of actionable proteins associated with FAT1 mutation, which provide important insight into possible prospective clinical investigation with therapeutic relevance. (Supported by grants from a pilot Winship Invests Grant of Emory University Winship Cancer Institute to GZC and NFS; and NIDCD/NIH intramural projects Z01-DC-00016, 73, 74 to ZC, and partially by the University of Illinois Cancer Center Biostatistics Shared Resource Core).
Citation Format: Zhuo Georgia Chen, Zhengjia Chen, Chao Zhang, Jianhong Chen, Dongsheng Wang, Nabil F. Saba, Zhong Chen. Identification of proteins associated with FAT1 mutations which potentially contribute to oncogenesis and progression of head and neck cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 321.