Developing a novel necroptosis-related signature to evaluate the prognostic and therapeutic characteristics of esophageal cancer

Mingzhi Chen; Tianzhen Hua; Lanjie Yang; Chunzhen Li; Shuhua Xu; Ji Zhu; Tiejun Zhao

Developing a novel necroptosis-related signature to evaluate the prognostic and therapeutic characteristics of esophageal cancer

Am J Transl Res. 2023 Aug 15;15(8):5425-5445. eCollection 2023.

Authors

Mingzhi Chen¹, Tianzhen Hua^{2

3}, Lanjie Yang⁴, Chunzhen Li⁴, Shuhua Xu⁵, Ji Zhu⁴, Tiejun Zhao⁴

Affiliations

¹ Department of Thoracic and Cardiovascular Surgery, Yixing Hospital Affiliated to Jiangsu University Yixing 214200, Jiangsu, China.
² Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital Beijing 100048, China.
³ Chinese PLA Medical School Beijing 100853, China.
⁴ Department of Thoracic Surgery, The First Affiliated Hospital of Naval Medical University Shanghai 200433, China.
⁵ Department of Surgery, Dongtai Hospital of Traditional Chinese Medicine Yancheng 224200, Jiangsu, China.

PMID: 37692951
PMCID: PMC10492067

Abstract

Background: The prognostic assessment and therapeutic interventions of esophageal cancer (ESCA) require novel molecular targets. The prognostic value of necroptosis, a specific mode of programmed cell death strongly linked to cancer progression, remains largely unexplored in ESCA. The primary goal of this research is to develop a necroptosis-based prognostic signature, which will represent the microenvironmental characteristics and prognosis of individuals diagnosed with ESCA.

Methods: Transcriptome data of ESCA samples from The Cancer Genome Atlas were utilized to screen for necroptosis-related long non-coding RNAs (NR-lncRNAs) and genes (NRGs). The research employed the least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis to identify prognostic candidates. Based on these analyses, a signature was developed in the training set and subsequently verified in the testing and entire sets. A clinicopathologic relevance assessment was carried out, after which a nomogram was established. The features of the immune microenvironment, functional pathways, mutational burden, checkpoint expression, and stemness of tumors were analyzed. Moreover, the sensitivity of individuals to immunotherapy and chemotherapy was compared for therapeutic guidance.

Results: A necroptosis-associated signature comprising two genes and eleven lncRNAs was constructed. High-risk patients showed worse prognosis and clinicopathologic features, with more tumor-infiltrating naïve B cells, CD4⁺ memory resting T cells, and regulatory T cells. Furthermore, stromal and ESTIMATE scores were decreased along with increased stemness scores and tumor mutational burden in high-risk individuals. For the quantitative prediction of the outcomes of individuals, a nomogram was established. High-risk individuals showed greater sensitivity to immunotherapy while low-risk individuals benefited more from conventional chemotherapeutic or targeted therapy.

Conclusion: A necroptosis-related prognostic signature was developed to study the tumor microenvironment, mutational burden, clinical features, and the treatment response of ESCA patients. This may contribute to precision medicine for ESCA.

Keywords: Necroptosis; esophageal cancer; immune microenvironment; lncRNA; prognosis.