Identification of Prognosis-Related Genes in Bladder Cancer Microenvironment across TCGA Database

Abstract

Background. Bladder cancer (BCa) is a common urothelial malignancy. The Cancer Genome Atlas (TCGA) database allows for an opportunity to analyze the relationship between gene expression and clinical outcomes in bladder cancer patients. This study is aimed at identifying prognosis-related genes in the bladder cancer microenvironment. Methods. Immune scores and stromal scores were calculated by applying the ESTIMATE algorithm. We divided bladder cancer patients into high and low groups based on their immune/stromal scores. Then, differentially expressed genes (DEGs) were identified in bladder cancer patients based on the TCGA database. We evaluated the correlation between immune/stromal scores and clinical characteristics as well as prognosis. Finally, we validated identified genes associated with bladder cancer prognosis through a cohort study in the Gene Expression Omnibus (GEO) database. Results. A higher stromal score was associated with female (vs. male p = 0.037 ), age > 65 (vs. age ≤ 65 p = 0.015 ), T3/4 (vs. T1/2, p < 0.001 ), N status p = 0.016 , and pathological high grade (vs. low grade P < 0.001 ). By analyzing DEGs, there were 1125 genes commonly upregulated, and 209 genes were commonly downregulated. Protein-protein interaction networks further showed the important protein that may be involved in the biological behavior and prognosis of BCa, such as FN1, CXCL12, CD3E, LCK, and ZAP70. A total of 14 DEGs were found to be associated with overall survival of bladder cancer. After validation by a cohort of 165 BCa cases with detailed follow-up information from GSE13507, 10 immune-associated DEGs were demonstrated to be predictive of prognosis in BCa. Among them, 5 genes have not been reported previously associated with the prognosis of BCa, including BTBD16, OLFML2B, PRRX1, SPINK4, and SPON2. Conclusions. Our study elucidated tight associations between stromal score and clinical characteristics as well as prognosis in BCa. Moreover, we obtained a group of genes closely related to the prognosis of BCa in the tumor microenvironment.

CXCL12 and CD3E as Indicators for Tumor Microenvironment Modulation in Bladder Cancer and Their Correlations With Immune Infiltration and Molecular Subtypes

“…Through ESTIMATE algorithm, we found that higher immune infiltration had improved survival, whereas higher stromal infiltration was associated with shorter OS. Contrary to our results, some studies showed there was no significant impact of stromal and immune scores on the survival of BLCA patients ( 22 , 23 ). The contrasted result was obtained because of the different cut-off value.…”

“…And we found that patients with high CXCL12 showed a poor prognosis and patients with high CD3E showed a better prognosis. Similar result was also observed by a previous study ( 23 ) while we further analyzed the correlations of hub genes with TICs and molecular subtype in BLCA. CXCL12, also known as stromal cell-derived factor-1 (SDF-1), is a crucial chemokine involved in physiological and pathological processes, including embryogenesis, neurogenesis, hematopoiesis, angiogenesis, lymphopoiesis, and inflammation ( 25 ).…”

Pan-Cancer Analysis of OLFML2B Expression and Its Association With Prognosis and Immune Infiltration

“…In addition, OLFML2B has been proven to be upregulated, presented a diagnostic and prognostic value ( Liu et al, 2019 ), and correlated with the TME in GC and HCC ( Ren et al, 2020 ) ( Liu et al, 2020 ). Furthermore, OLFML2B is bound up with tumorigenesis and prognosis in bladder cancer ( Zhao et al, 2020 ). OLFML2B can serve as a potential prognostic biomarker for osteosarcoma ( Yao et al, 2021 ).…”

SPINKs in Tumors: Potential Therapeutic Targets

“…In multivariate regression, SPINK4 was confirmed as an independent indicator of low survival in CRC patients (115). In addition, SPINK4 is related to the prognosis of BCa, reflecting the good overall survival rate of BCa (116).…”