TY - JOUR AU - Mai, Zihang AU - Yuan, Jianye AU - Yang, Hong AU - Fang, Shuogui AU - Xie, Xiuying AU - Wang, Xinye AU - Xie, Jiaxin AU - Wen, Jing AU - Fu, Jianhua T1 - Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer PY - 2022/08/22/ AB - Identification of molecular subtypes that reflect different prognoses and treatment responses, especially immune checkpoint inhibitors (ICIs) in esophageal squamous cell carcinoma (ESCC), is essential for treatment decisions. We performed targeted sequencing in 201 patients with ESCC to discover genetic subtypes and validate our findings via multiple data sets. We identified 3 driver genes (FCGBP, GRIN2B, and FRY), and recurrent truncating mutations in FRY impaired its tumor-suppressive function and promoted tumor proliferation. A 3-gene mutation signature (FAT1, FAT3, and FRY) recognized a molecular subtype named “FAT/FRY” with frequent Hippo pathway–related mutations. In multiple ESCC cohorts, the patients with the FAT/FRY subtype had poorer prognosis than did patients in the WT group. Transcriptome analysis indicated that the FAT/FRY subtype was characterized by inactivation of the Hippo pathway, hypoxia, chemoresistance, higher infiltration of CD8+ T cells and activated DCs, and a transcriptome similar to that of cancer responders. Furthermore, the 3-gene signature predicted better survival for patients treated with ICIs, partially explained by its positive correlation with the tumor mutation burden and neoantigen burden. The 3-gene signature is a biomarker to recognize the FAT/FRY molecular subtype, evaluate prognosis, and select potential beneficiaries of ICIs in ESCC. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.155218 VL - 7 IS - 16 UR - https://doi.org/10.1172/jci.insight.155218 PB - The American Society for Clinical Investigation ER -