Development and Validation of a Prognostic Autophagy-Related Gene Pair Index Related to Tumor-Infiltrating Lymphocytes in Early-Stage Lung Adenocarcinoma.

Zi-Hao Wang,Lin-Lin Ye,Wen-Bei Peng,Qian-Qian Xue,Xuan Xiang,Yu Li,Si-Yu Zhang,Yi-Ran Niu,Pei Zhang,Xiao-Shan Wei,Qiong Zhou

doi:10.3389/fcell.2021.719011

Abstract

The role of autophagy in lung cancer is context-dependent and complex. Recent studies have reported the important role of autophagy in tumor immune escape. However, the association between autophagy and tumor-infiltrating lymphocytes (TILs) in early-stage lung adenocarcinoma (LUAD) remains unclear. In this study, we aimed to develop and validate the autophagy-related gene pair index (ATGPI) and autophagy clinical prognostic index (ACPI) in multiple LUAD cohorts, including The Cancer Genome Atlas (TCGA) cohort, Gene Expression Omnibus cohorts, and one cohort from Union Hospital, Wuhan (UH cohort), using a Cox proportional hazards regression model with the least absolute shrinkage and selection operator. Multivariate Cox regression analysis demonstrated that there was a significant difference in overall survival (OS) between patients with high and low ATGPI in the testing [hazard ratio (HR) = 1.97; P < 0.001] and TCGA validation (HR = 2.25; P < 0.001) cohorts. Time-dependent receiver operating characteristic curve analysis was also performed. We found that high ATGPI could accurately identify patients with early-stage LUAD with shorter OS, with the areas under the curve of 0.703 and 0.676 in the testing and TCGA validation cohorts, respectively. Concordance index (C-index) was used to evaluate the efficiency of ATGPI and ACPI. The C-index of ACPI was higher than that of ATGPI in the testing (0.71 vs. 0.66; P < 0.001), TCGA validation (0.69 vs. 0.65; P = 0.028), and UH (0.80 vs. 0.70; P = 0.015) cohorts. TIL analysis demonstrated that the proportions of tumor-infiltrating CD4+ T cells were lower in the high-ATGPI group than in the low-ATGPI group in both the TCGA validation and UH cohorts. These results indicate the potential clinical use of ATG signatures which are associated with TILs, in identifying patients with early-stage LUAD with different OS.

Highlights

Macroautophagy is a highly conserved catabolic process that involves the formation of autophagosomes, growth of double membranes, merging with lysosomes, and disintegration of engulfed cellular proteins and organelles (Levine and Kroemer, 2008; Levy et al, 2017)
We first constructed a tumor-infiltrating lymphocytes (TILs)-related prognostic biomarker based on autophagyrelated gene pairs (ATGPs) for patients with early-stage lung adenocarcinoma (LUAD) by combining multiple gene expression datasets
To construct a robust signature, data from 12 Gene Expression Omnibus (GEO) LUAD datasets were randomly divided into training and testing datasets

Summary

Introduction

Macroautophagy (referred to here as autophagy) is a highly conserved catabolic process that involves the formation of autophagosomes, growth of double membranes, merging with lysosomes, and disintegration of engulfed cellular proteins and organelles (Levine and Kroemer, 2008; Levy et al, 2017). Inactivation of the essential autophagy gene ATG5 accelerates the early phases of non-small cell lung cancer (NSCLC) oncogenesis (Rao et al, 2014). Multiple factors, including circular RNA, REV-ERB agonists, and copper, can function as autophagy regulators to modulate the proliferation, migration, and invasion of lung cancer (Chen et al, 2020; Shen et al, 2020; Tsang et al, 2020). These findings demonstrate the biological significance of autophagy in lung cancer. Few studies have focused on the potential of ATG genes in predicting survival of patients with early-stage lung adenocarcinoma (LUAD)

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