Identification of four metabolic subtypes and key prognostic markers in lung adenocarcinoma based on glycolytic and glutaminolytic pathways

Abstract

Background Glucose and glutamine are the main energy sources for tumor cells. Whether glycolysis and glutaminolysis play a critical role in driving the molecular subtypes of lung adenocarcinoma (LUAD) is unknown. This study attempts to identify LUAD metabolic subtypes with different characteristics and key genes based on gene transcription profiling data related to glycolysis and glutaminolysis, and to construct prognostic models to facilitate patient outcome prediction. Methods LUAD related data were obtained from the Cancer Genome Atlas and Gene Expression Omnibus, including TCGA-LUAD, GSE42127, GSE68465, GSE72094, GSE29013, GSE31210, GSE30219, GSE37745, GSE50081. Unsupervised consensus clustering was used for the identification of LUAD subtypes. Differential expression analysis, weighted gene co-expression network analysis (WGCNA) and CytoNCA App in Cytoscape 3.9.0 were used for the screening of key genes. The Cox proportional hazards model was used for the construction of the prognostic risk model. Finally, qPCR analysis, immunohistochemistry and immunofluorescence colocalization were used to validate the core genes of the model. Result This study identified four distinct characterized LUAD metabolic subtypes, glycolytic, glutaminolytic, mixed and quiescent types. The glycolytic type had a worse prognosis than the glutaminolytic type. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) were identified as hub genes driving the glycolytic/glutaminolytic LUAD. In addition, the risk assessment model constructed based on three genes (SPP1, SLC2A1 and AGER) had good predictive performance and could be validated in multiple independent external LUAD cohorts. These three genes were differentially expressed in LUAD and lung normal tissues, and might be potential prognostic markers for LUAD. Conclusion LUAD can be classified into four different characteristic metabolic subtypes based on the glycolysis- and glutaminolysis-related genes. Nine genes (CXCL8, CNR1, AGER, ALB, S100A7, SLC2A1, TH, SPP1, LEP) may play an important role in the subtype-intrinsic drive. This metabolic subtype classification, provides new biological insights into the previously established LUAD subtypes.

Comprehensive analysis based on glycolytic and glutaminolytic pathways signature for predicting prognosis and immunotherapy in ovarian cancer

“…According to previous study 21 , the “ConsensusClusterPlus” R package was utilized to perform consensus clustering of OV samples. Ultimately, according to the median expression level of co-expressed metabolic genes, we classified the OV patients into four completely distinct metabolic subtypes: quiescent type, glycolytic type, glutaminolytic type, and mixed type.…”

“…Firstly, the "limma" package was applied to discover the dysregulated genes between the glutaminolytic type and glycolytic type according to | Log 2 FC | > 0.585 and P. adj < 0.05 standard. Next, consistent with the approach that Zhang et al has adopted [21], the "WGCNA" package was applied to pinpoint the key genes associated with metabolic variances between the glutaminolytic and glycolytic subtypes. The "ClusterProfiler" package was employed to conduct Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of the key metabolic genes.…”

“…As revealed in Figure 2A, the co-expressed genes in C2 (characterized as glycolytic genes, including ALDOA, ENO1, GAPDH, GPI, LDHA, PGK1, PKM, TPI1) be categorized as the glycolytic metabolic pathway, and the co-expressed genes in C3 (characterized as glutaminolytic genes, including ARG1, ASRGL1, DAO, FAH, GAD2, NOS1, NOS2, PRODH2) belong to the glutaminolytic metabolic pathway. Patients were delineated into four metabolic subtypes based on the two types of co-expressed metabolism gene sets, as described approach in the earlier literature [21] (Figure 2B), including quiescent subtype, glycolytic subtype, glutaminolytic subtype, and mixed subtype. The gene expression levels between the four metabolic subtypes were shown in Figure 2C.…”