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 7

Molecular subtype–based treatment strategy.

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Molecular subtype–based treatment strategy. (A and B) Bar chart showing ...
(A and B) Bar chart showing that the FAT/FRY subgroup had higher rates of durable clinical benefit than the WT group in both ICI data sets. (C and D) Survival differences of the FAT/FRY subgroup and WT subgroup in Matthew Hellmann’s (13) and Diana Miao’s (12) ICI cohorts. P values were calculated by log-rank tests. (E and F) The area under the time-dependent received operator characteristic curve of the 3-gene signature and TMB to predict post-ICI prognosis in the cohorts from refs. 12 and 13. (G) Box plot indicating that the significant correlations of the 3-gene signature and TMB in 2 ICI and 2 ESCC cohorts. (H) Box plot showing that the FAT/FRY subgroup had higher neoantigen burden but not PD-L1 expression than the WT subgroup. (I) Box plot displaying differences of drug responses in FAT/FRY-mutant ESCC cell lines and WT cell lines in the GDSC pharmacogenomics database. *P < 0.05, **P < 0.01, ***P < 0.001. P values in G–I 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.