Alteration in glycolytic/cholesterogenic gene expression is associated with bladder cancer prognosis and immune cell infiltration

Abstract

Background Oncogenic metabolic reprogramming contributes to tumor growth and immune evasion. The intertumoral metabolic heterogeneity and interaction of distinct metabolic pathways may determine patient outcomes. In this study, we aim to determine the clinical and immunological significance of metabolic subtypes according to the expression levels of genes related to glycolysis and cholesterol-synthesis in bladder cancer (BCa). Methods Based on the median expression levels of glycolytic and cholesterogenic genes, patients were stratified into 4 subtypes (mixed, cholesterogenic, glycolytic, and quiescent) in an integrated cohort including TCGA, GSE13507, and IMvigor210. Clinical, genomic, transcriptomic, and tumor microenvironment characteristics were compared between the 4 subtypes. Results The 4 metabolic subtypes exhibited distinct clinical, molecular, and genomic patterns. Compared to quiescent subtype, mixed subtype was more likely to be basal tumors and was significantly associated with poorer prognosis even after controlling for age, gender, histological grade, clinical stage, and molecular phenotypes. Additionally, mixed tumors harbored a higher frequency of RB1 and LRP1B copy number deletion compared to quiescent tumors (25.7% vs. 12.7 and 27.9% vs. 10.2%, respectively, both adjusted P value< 0.05). Furthermore, aberrant PIK3CA expression level was significantly correlated with those of glycolytic and cholesterogenic genes. The quiescent subtype was associated with lower stemness indices and lower signature scores for gene sets involved in genomic instability, including DNA replication, DNA damage repair, mismatch repair, and homologous recombination genes. Moreover, quiescent tumors exhibited lower expression levels of pyruvate dehydrogenase kinases 1-3 (PDK1-3) than the other subtypes. In addition, distinct immune cell infiltration patterns were observed across the 4 metabolic subtypes, with greater infiltration of M0/M2 macrophages observed in glycolytic and mixed subtypes. However, no significant difference in immunotherapy response was observed across the 4 metabolic subtypes. Conclusion This study proposed a new metabolic subtyping method for BCa based on genes involved in glycolysis and cholesterol synthesis pathways. Our findings may provide novel insight for the development of personalized subtype-specific treatment strategies targeting metabolic vulnerabilities.

DNA Damage Repair-Related Genes Signature for Immune Infiltration and Outcome in Cervical Cancer

“…It is conceivable that the stratified model, which first stratified patients into subgroups, and then applied individual based risk stratification, can be used to predict biologically relevant clinical outcomes. The concept of “subtype specific” biomarkers has been successfully applied to improve the prognosis of many kinds of cancers ( Hu et al, 2021 ; Ahearn et al, 2022 ; Zhang et al, 2022 ). Therefore, integrating subtype analysis and individual based models may be a promising method to develop clinically relevant biomarkers.…”

Analysis of copy number alterations in bladder cancer stem cells revealed a prognostic role of LRP1B

“…LRP1B role as a candidate tumor suppressor also for bladder cancer has been proposed several years ago [ 25 ]; however, its function still remains to be fully elucidated. A lower frequency of its copy-number deletions was newly associated with a specific subtype of bladder cancer (quiescent type) that exhibited the best overall survival [ 26 ]. Our TCGA analysis confirmed its crucial role, for the first time linked to short-term prognosis (1-year survival).…”

Classification and Prognostic Characteristics of Hepatocellular Carcinoma Based on Glycolysis Cholesterol Synthesis Axis

“…Molecular Subtypes. Previous studies have found a relationship between glycolytic/cholesterol metabolism and immune infiltration [35,36]. erefore, we compared the distribution of our molecular subtypes to the previous immune subtypes.…”