Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer
Zihang Mai, … , Jing Wen, Jianhua Fu
Zihang Mai, … , Jing Wen, Jianhua Fu
Published August 22, 2022
Citation Information: JCI Insight. 2022;7(16):e155218. https://doi.org/10.1172/jci.insight.155218.
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Research Article Gastroenterology Oncology

Inactivation of Hippo pathway characterizes a poor-prognosis subtype of esophageal cancer

Abstract

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.

Authors

Zihang Mai, Jianye Yuan, Hong Yang, Shuogui Fang, Xiuying Xie, Xinye Wang, Jiaxin Xie, Jing Wen, Jianhua Fu

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Figure 6

Molecular and immune microenvironment characteristics of FAT/FRY subtype ESCC tumors.

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Molecular and immune microenvironment characteristics of FAT/FRY subtype...
(A) Gene set enrichment analysis plot showing that genes involved in the Hippo pathway were dysregulated in the FAT/FRY subgroup. (B) The expression level of core genes of the Hippo pathway and targets of Hippo/YAP in our discovery set (n = 90). (C) Box plot showing the differences in the relative abundance of CD8+ T cells, activated DCs, eosinophils, and γδ T cells between both groups in the TCGA-ESCC and GSE47404 data sets. (D) Heatmap displaying the relative abundances of major immune cell types in TCGA cohort. (E and F) Validation of enrichment of CD8+ TILs by IHC in our discovery cohort (n = 170). (G) Box plot showing the differences in the expression of IFN-γ response signature between the FAT/FRY and WT groups. (H) Transcriptomic similarities of our ESCC subtypes and response groups in 3 ICI cohorts: Pei-Ling Chen et al. (55), Willy Hugo et al. (42), and Alexandra Snyder et al. (56). A smaller P value indicates a higher transcriptomic similarity between the 2 groups. The P values in B–G were calculated by Wilcoxon test. The box plots depict the minimum and maximum values (whiskers), the upper and lower quartiles, and the median. The length of the box represents the interquartile range. NR, nonresponse; R, response.