Abstract
BackgroundThe early-stage lung adenocarcinoma (LUAD) rate has increased with heightened public awareness and lung cancer screening implementation. Lipid metabolism abnormalities are associated with lung cancer initiation and progression. However, the comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for early-stage LUAD remain obscure.MethodsLMRGs were extracted from Gene Set Enrichment Analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Samples from The Cancer Genome Atlas (TCGA) were used as training cohort, and samples from four Gene Expression Omnibus (GEO) datasets were used as validation cohorts. The LUAD recurrence-associated LMRG molecular pattern and signature was constructed through unsupervised consensus clustering, time-dependent receiver operating characteristic (ROC), and least absolute shrinkage and selection operator (LASSO) analyses. Kaplan-Meier, ROC, and multivariate Cox regression analyses and prognostic meta-analysis were used to test the suitability and stability of the signature. We used Gene Ontology (GO), KEGG pathway, immune cell infiltration, chemotherapy response analyses, gene set variation analysis (GSVA), and GSEA to explore molecular mechanisms and immune landscapes related to the signature and the potential of the signature to predict immunotherapy or chemotherapy response.ResultsFirst, two LMRG molecular patterns were established, which showed diverse prognoses and immune infiltration statuses. Then, a 12-gene signature was identified, and a risk model was built. The signature remained an independent prognostic parameter in multivariate Cox regression and prognostic meta-analysis. In addition, this signature stratified patients into high- and low-risk groups with significantly different recurrence rates and was well validated in different clinical subgroups and several independent validation cohorts. The results of GO and KEGG analyses and GSEA showed that there were differences in multiple lipid metabolism, immune response, and drug metabolism pathways between the high- and low-risk groups. Further analyses revealed that the signature-based risk model was related to distinct immune cell proportions, immune checkpoint parameters, and immunotherapy and chemotherapy response, consistent with the GO, KEGG, and GSEA results.ConclusionsThis is the first lipid metabolism-based signature for predicting recurrence, and it could provide vital guidance to achieve optimized antitumor for immunotherapy or chemotherapy for early-stage LUAD.
Highlights
As the leading cause of cancer-related incidence and mortality, lung cancer accounts for approximately 20% of global cancerspecific deaths [1]
Based on 334 early-stage Lung adenocarcinoma (LUAD) patients from the The Cancer Genome Atlas (TCGA) database, we performed univariate Cox regression analysis and found that 83 lipid metabolism-related genes (LMRGs) were significantly associated with cancer recurrence (Table S2, p
The number of genes missing from the validation group was small, we still performed this analysis on the validation groups by their optimal k values separately
Summary
As the leading cause of cancer-related incidence and mortality, lung cancer accounts for approximately 20% of global cancerspecific deaths [1]. Lung adenocarcinoma (LUAD) is the most common pathologic type, accounting for almost 40% of all lung cancer subtypes, and is characterized by rapid progression, severe prognosis, and early recurrence [2]. The overall survival (OS) of LUAD patients remains unfavorable, with a 5-year OS rate of 19% [3]. Even for early-stage LUAD disease, the recurrence rate remains 30–45% within 5 years after surgery [4, 5]. The incidence of early-stage LUAD has increased rapidly with heightened public awareness and implementation of lung cancer screening [6]. The early-stage lung adenocarcinoma (LUAD) incidence has increased with heightened public awareness and lung cancer screening implementation. The comprehensive features and clinical significance of the immunometabolism landscape and lipid metabolism-related genes (LMRGs) in cancer recurrence for earlystage LUAD remain obscure
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