Identification of an Individualized Metabolism Prognostic Signature and Related Therapy Regimens in Early Stage Lung Adenocarcinoma.
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ABSTRACT: Objective
The choice of adjuvant therapy for early stage lung adenocarcinoma (LUAD) remains controversial. Identifying the metabolism characteristics leading to worse prognosis may have clinical utility in offering adjuvant therapy.Methods
The gene expression profiles of LUAD were collected from 22 public datasets. The patients were divided into a meta-training cohort (n = 790), meta-testing cohort (n = 716), and three independent validation cohorts (n = 345, 358, and 321). A metabolism-related gene pair index (MRGPI) was trained and validated in the cohorts. Subgroup analyses regarding tumor stage and adjuvant chemotherapy (ACT) were performed. To explore potential therapeutic targets, we performed in silico analysis of the MRGPI.Results
Through machine learning, MRGPI consisting of 12 metabolism-related gene pairs was constructed. MRGPI robustly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I or II disease in all cohorts. Multivariable analysis confirmed that MRGPI was an independent prognostic factor. ACT could not improve prognosis in high-risk patients with stage I disease, but could improve prognosis in the high-risk patients with stage II disease. In silico analysis indicated that B3GNT3 (overexpressed in high-risk patients) and HSD17B6 (down-expressed in high-risk patients) may make synergic reaction in immune evasion by the PD-1/PD-L1 pathway. When integrated with clinical characteristics, the composite clinical and metabolism signature showed improved prognostic accuracy.Conclusions
MRGPI could effectively predict prognosis of the patients with early stage LUAD. The patients at high risk may get survival benefit from PD-1/PD-L1 blockade (stage I) or combined with chemotherapy (stage II).
SUBMITTER: Hu J
PROVIDER: S-EPMC8113858 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Lung adenocarcinoma (LUAD) remains the most common type of lung cancer and is the main cause of cancer-related death worldwide. Reprogramming of glucose metabolism plays a crucial role in tumorigenesis and progression. However, the regulation of glucose metabolism is still being explored in LUAD. Determining the underlying clinical value of glucose metabolism will contribute in increasing clinical interventions. Our study aimed to conduct a comprehensive analysis of the landscape of glucose metabolism-related genes in LUAD and develop a prognostic risk signature. Methods: We extracted the RNA-seq data and relevant clinical variants from The Cancer Genome Atlas (TCGA) database and identified glucose metabolism-related genes associated with the outcome by correlation analysis. To generate a prognostic signature, least absolute shrinkage and selection operator (LASSO) Cox regression analysis was performed. Results: Finally, ten genes with expression status were identified to generate the risk signature, including FBP2, ADH6, DHDH, PRKCB, INPP5J, ABAT, HK2, GNPNAT1, PLCB3, and ACAT2. Survival analysis indicated that the patients in the high-risk group had a worse survival than those in the low-risk group, which is consistent with the results in validated cohorts. And receiver operating characteristic (ROC) curve analysis further validated the prognostic value and predictive performance of the signature. In addition, the two risk groups had significantly different clinicopathological characteristics and immune cell infiltration status. Notably, the low-risk group is more likely to respond to immunotherapy. Conclusion: Overall, this study systematically explored the prognostic value of glucose metabolism and generated a prognostic risk signature with favorable efficacy and accuracy, which help select candidate patients and explore potential therapeutic approaches targeting the reprogrammed glucose metabolism in LUAD.
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