Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma

Mengnan Zhao; Ming Li; Yuansheng Zheng; Zhengyang Hu; Jiaqi Liang; Guoshu Bi; Yunyi Bian; Qihai Sui; Cheng Zhan; Miao Lin; Qun Wang

doi:10.7150/jca.68568

Identification and analysis of a prognostic ferroptosis and iron-metabolism signature for esophageal squamous cell carcinoma

J Cancer. 2022 Mar 6;13(5):1611-1622. doi: 10.7150/jca.68568. eCollection 2022.

Authors

Mengnan Zhao¹, Ming Li¹, Yuansheng Zheng¹, Zhengyang Hu¹, Jiaqi Liang¹, Guoshu Bi¹, Yunyi Bian¹, Qihai Sui¹, Cheng Zhan¹, Miao Lin¹, Qun Wang¹

Affiliation

¹ Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Abstract

Background: The role of ferroptosis in esophageal squamous cell carcinoma (ESCC) is still unclear. Methods: The association of iron metabolism and ferroptosis-related genes with the prognosis, copy number variation (CNV), TMB, and immune cell infiltration of ESCC was explored using data from the GEO and TCGA database and validated by immunofluorescence in 112 ESCC patients from our center. The potential anti-cancer drugs and compounds from the GDSC and the Connectivity Map database were also screened. Results: A total of 117 iron metabolism and ferroptosis-related genes were identified. We found the expressions of PRNP, SLC3A2, SLC39A8, and SLC39A14 negatively related to the prognosis of ESCC patients, while ATP6V0A1 and LCN2 were opposite, which was validated in 112 ESCC samples from our center. And a prognostic signature was constructed based on their expressions and Cox regression coefficient (β). The low-score group exhibited a significantly worse OS. Besides, analysis of 179 ESCC samples from GSE53625 revealed that patients of poorly differentiation, more than 60 years, T4 stage, advanced N stage, advanced stage, and adjuvant therapy also exhibited a significantly shorter OS, based on which a nomogram to predict the OS was established. Moreover, the low-score group exhibited significantly higher CNV and TMB and more frequent mutations of TP53, MUC16, and NOTCH1. Higher proportion of Macrophages M2, and lower proportion of T cells follicular helper were observed in the low-score group. We discovered that AZD7762, Sunitinib, Cytarabine, Docetaxel, Vinblastine, and Elesclomol exhibited lower IC50 in the low-score group. And 20 potential compounds were identified from the CMap database. Conclusions: Six iron metabolism and ferroptosis-related genes were associated with the prognosis, CNV, TMB, and immune cell infiltration of ESCC. Some potential anti-cancer drugs and compounds may be helpful for OS.

Keywords: Connectivity Map database; GDSC database; GEO database; TCGA database; TMB; esophageal squamous cell carcinoma.