TP53-related signature for predicting prognosis and tumor microenvironment characteristics in bladder cancer: A multi-omics study

Abstract

Background: The tumor suppressor gene TP53 is frequently mutated or inactivated in bladder cancer (BLCA), which is implicated in the pathogenesis of tumor. However, the cellular mechanisms of TP53 mutations are complicated, yet well-defined, but their clinical prognostic value in the management of BLCA remains controversial. This study aimed to explore the role of TP53 mutation in regulating the tumor microenvironment (TME), elucidate the effects of TP53 activity on BLCA prognosis and immunotherapy response.Methods: A TP53-related signature based on TP53-induced and TP53-repressed genes was used to construct a TP53 activity-related score and classifier. The abundance of different immune cell types was determined using CIBERSORT to estimate immune cell infiltration. Moreover, the heterogeneity of the tumor immune microenvironment between the high and low TP53 score groups was further evaluated using single-cell mass cytometry (CyTOF) and imaging mass cytometry (IMC). Moreover, pathway enrichment analysis was performed to explore the differential biological functions between tumor epithelial cells with high and low TP53 activity scores. Finally, the receptor–ligand interactions between immune cells and tumor epithelial cells harboring distinct TP53 activity were analyzed by single-cell RNA-sequencing.Results: The TP53 activity-related gene signature differentiated well between TP53 functional retention and inactivation in BLCA. BLCA patients with low TP53 scores had worse survival prognosis, more TP53 mutations, higher grade, and stronger lymph node metastasis than those with high TP53 scores. Additionally, CyTOF and IMC analyses revealed that BLCA patients with low TP53 scores exhibited a potent immunosuppressive TME. Consistently, single-cell sequencing results showed that tumor epithelial cells with low TP53 scores were significantly associated with high cell proliferation and stemness abilities and strongly interacted with immunosuppressive receptor–ligand pairs.Conclusion: BLCA patients with low TP53 scores have a worse prognosis and a more immunosuppressive TME. This TP53 activity-related signature can serve as a potential prognostic signature for predicting the immune response, which may facilitate the development of new strategies for immunotherapy in BLCA.

Comprehensive identification of onco-exaptation events in bladder cancer cell lines revealed L1PA2-SYT1 as a prognosis-relevant event

“…To investigate whether the high expression of L1PA2-SYT1 is associated with poor prognosis in cancer, we retrieved RNA-seq data (SRA: PRJNA891747) from 52 muscle-invasive bladder cancer patients with follow-up information as the validation group. 29 Again, we that found patients having L1PA2-SYT1 showed higher level of SYT1 expression, which validated the driving effect of L1PA2 on SYT1 ( Figures 2 A and 5 D). Also, the existence of L1PA2-SYT1 is associated with poor overall survival of patients ( Figure 5 E).…”

Identification of tumor immunophenotypes associated with immunotherapy response in bladder cancer

“…GXMU‐BLCA cohort consisted of 44 males and 8 females, including 13 patients with lymph node metastasis and 29 patients without lymph node metastasis. According to the TNM staging system of bladder cancer, 34 patients were categorized I–II stage, 16 patients were categorized III–IV, leaving 2 unknown 17 . RNA‐seq of tumor samples was used in the analysis.…”

Small Cajal Body-Specific RNA12 Promotes Carcinogenesis through Modulating Extracellular Matrix Signaling in Bladder Cancer

“…Bulk RNA sequencing was performed as previously described [21]. FastQC (URL: https://www.bioinformatics.babraham.ac.uk/projects/fastqc/, accessed on 15 May 2023) was applied to evaluate the quality of the paired-end RNA seq data.…”