Genome-Wide DNA Methylation and Gene Expression Profiling Characterizes Molecular Subtypes of Esophagus Squamous Cell Carcinoma for Predicting Patient Survival and Immunotherapy Efficacy

Abstract

Background: Immunotherapy is recently being used to treat esophageal squamous cell carcinoma (ESCC); however, response and survival benefits are limited to a subset of patients. A better understanding of the molecular heterogeneity and tumor immune microenvironment in ESCC is needed for improving disease management. Methods: Based on the DNA methylation and gene expression profiles of ESCC patients, we identify molecular subtypes of patients and construct a predictive model for subtype classification. The clinical value of molecular subtypes for the prediction of immunotherapy efficacy is assessed in an independent validation cohort of Chinese ESCC patients who receive immunotherapy. Results: We identify two molecular subtypes of ESCC (S1 and S2) that are associated with distinct immune-related pathways, tumor microenvironment and clinical outcomes. Accordingly, S2 subtype patients had a poorer prognosis. A 15-gene expression signature is developed to classify molecular subtypes with an overall accuracy of 94.7% (89/94, 95% CI: 0.880–0.983). The response rate of immunotherapy is significantly higher in the S1 subtype than in the S2 subtype patients (68.75% vs. 25%, p = 0.028). Finally, potential target drugs, including mitoxantrone, are identified for treating patients of the S2 subtype. Conclusions: Our findings demonstrated that the identified molecular subtypes constitute a promising prognostic and predictive biomarker to guide the clinical care of ESCC patients.

Nomogram-Based Survival Predictions and Treatment Recommendations for Locally Advanced Esophageal Squamous Cell Carcinoma Treated with Upfront Surgery

“…The predominant imaging method is CT in China, while PET-CT is nowadays widely used in follow-up in Western counties [ 27 ]. Fifth, clinicopathological factors on the molecular or genetic level were absent in this study, and explorations on gene mutation profile, tumor microenvironment, and signaling pathways are suggested for further research [ 28 , 29 , 30 , 31 ].…”

Biomarkers and experimental models for cancer immunology investigation

“…47 By calculating the scores of a series of key gene phenotypes within the CIMP subtype, predictions can be made regarding the therapeutic prognosis of patients. 47,148,149 Besides, ICB response prediction models utilizing DNA methylation profiles have emerged for several cancer types including melanoma, 150 esophagus carcinoma, 48 NSCLC, 151 glioma, 152 and bladder cancer. 153 However, despite the potential of DNA methylation being a reliable biomarker in various cancers, fundamental exploration is still needed.…”

Molecular classification of esophageal squamous cell carcinoma based on immunogenic cell death related damage-associated molecular pattern gene signature

“…More and more studies have realized that molecular heterogeneity is associated with the tumor recurrence and metastasis after treatment, and even resistance to treatment [13,14]. A better understanding of the molecular heterogeneity in ESCC is important for designing novel immunotherapies to improve the response and prognosis.…”

“…A better understanding of the molecular heterogeneity in ESCC is important for designing novel immunotherapies to improve the response and prognosis. Although some predictive models related to immunotherapy have been constructed to elaborate subtypes of ESCC [14,15], ICD-associated DAMPs have hardly been used to construct classi cation model. In this study, we intended to identify DAMPs related molecular subtypes in ESCC, elaborate the function, genome, immune microenvironment differences among different subtypes, and nally evaluate the predictive power of this classi cation model to immunotherapy response.…”