Potential roles of FAT1 somatic mutation in progression of head and neck cancer.

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. It disturbs patients’ vital upper aero-digestive function. Treatment outcomes for patients with HNSCC remain poor in past decades due to the lack of effective therapeutic options, thereby, discovery and evaluation of new medications are of tremendous importance for improving patients’ survival. Human papillomavirus (HPV) status remains one of strong indicators of survival, however, HPV-unrelated disease carrying a 5-year overall survival (OS) rate of less than 50% [2]. The challenges in effectively treating HNSCC are attributed to its extreme heterogeneity as far as anatomic locations and genetic aberrations. Major gaps in understanding the biology of disease continue to be the main reason behind the paucity of effective therapeutic interventions. FAT1 encodes a member of the cadherin-like protein family. Under normal physiological conditions, FAT1 serves as a molecular “brake” on mitochondrial respiration [3] and acts as a receptor for a signaling pathway regulating cell-cell contact interaction and planar cell polarity [4, 5]. Loss of fat leads to cell cycle dysregulation and hyperproliferation in Drosophila larval imaginal discs [6]. Recently, FAT1 mutations were identified in human cancers and may contribute to Wnt activation, suggesting that FAT1 may serve as a tumor suppressor in human cells [7]. The FAT1 mutant was found to inactivate the Hippo regulatory complex, which leads to activation of YAP1 in HNSCC as reported by Martin et al. They also indicated that the FAT1 gene alteration rate was as high as 29.8% in HNSCC, which is the highest among solid tumors [8]. FAT1 mutation was reported to be more common in HPV-negative (HPV−) than in HPV-positive (HPV+) HNSCC (28% vs. 2.8%). Mann et al., examined 16 HNSCC cell lines and reported a FAT1 mutation rate of 43% [9]. One recent study on Research Perspective