Identifying key mutations of radioresponsive genes in esophageal squamous cell carcinoma

Xin Xu; Yuming Wang; Yongrui Bai; Jun Lu; Yuntao Guo; Xiaohang Wang; Ling Rong; Jianmin Tang; Xiumei Ma; Jun Ma; Lei Zhang

doi:10.3389/fimmu.2022.1001173

Identifying key mutations of radioresponsive genes in esophageal squamous cell carcinoma

Front Immunol. 2022 Sep 2:13:1001173. doi: 10.3389/fimmu.2022.1001173. eCollection 2022.

Authors

Xin Xu¹, Yuming Wang², Yongrui Bai¹, Jun Lu³, Yuntao Guo⁴, Xiaohang Wang¹, Ling Rong¹, Jianmin Tang¹, Xiumei Ma¹, Jun Ma⁵, Lei Zhang¹

Affiliations

¹ Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Thoracic Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Research, Medical Laboratory of Nantong Zhongke, Nantong, China.
⁴ Department of Bioinformatics, Medical Laboratory of Nantong Zhongke, Nantong, China.
⁵ Eye Institute, Eye & Ear, Nose, and Throat Hospital, Shanghai Medical College, Fudan University, Shanghai, China.

Abstract

Background: Radiotherapy plays an important effect on the standard therapy of esophageal squamous cell carcinoma (ESCC). However, the efficacy of the therapy is limited and a few patients do not achieve satisfactory treatment results due to the existence of radiation resistance. Therefore, it is necessary to identify the potential predictive biomarkers and treatment targets for ESCC.

Methods: We performed the whole-exome sequencing to determine the germline and somatic mutations in ESCC. Functional enrichment and pathway-based protein-protein interaction analyses were used to ascertain potential regulatory networks. Cell survival and cell death after treatment with radiotherapy were determined by CCK-8 and LDH release assays in ESCC cells. The correlations of NOTCH1 and tumor immune infiltration were also analyzed in ESCC.

Results: Our results showed that 344 somatic and 65 germline differentially mutated genes were detected to be radiosensitivity-related loci. The tumor mutational burdens (TMB) or microsatellite instability (MSI) were not significantly correlated with the response to radiotherapy in ESCC patients. Pathway-based protein-protein interaction analyses implied several hub genes with most nodes (such as PIK3CA, NOTCH1, STAT3 and KDR). The in vitro studies showed that the knockdown of NOTCH1 inhibited cell survival and rendered more cell death after the treatment with radiotherapy in ESCC cells, while NOTCH1 overexpression had the opposite effects. Moreover, NOTCH1, frequently up-regulated in ESCC, was negatively correlated with activated B cell and immature dendritic cell in ESCC. High expression of NOTCH1 was accompanied with the low levels of some immunotherapy-related cells, including CD8(+) T cells and NK cells.

Conclusions: These results indicate the differences of the germline mutations and somatic mutations between the radiosensitive and radioresistence groups in ESCC and imply that NOTCH1 plays important roles in regulating the radiosensitivity of ESCC. The findings might provide the biomarkers and potential treatment targets for improving the sensitivity to radiotherapy in ESCC.

Keywords: ESCC; NOTCH1; immune; radiotherapy; survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

CD8-Positive T-Lymphocytes / pathology
Class I Phosphatidylinositol 3-Kinases / genetics
Esophageal Neoplasms* / genetics
Esophageal Neoplasms* / radiotherapy
Esophageal Squamous Cell Carcinoma* / genetics
Esophageal Squamous Cell Carcinoma* / radiotherapy
Humans
Mutation
Sincalide / genetics

Substances

Class I Phosphatidylinositol 3-Kinases
Sincalide