Identification of pyroptosis-related molecular subtypes and development of a subtype-derived six-gene prognostic signature for bladder cancer
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An Orthotopic Bladder Tumor Model and the Evaluation of Intravesical saRNA Treatment
Published on: July 28, 2012
Shuai Tang1,2,3, Ximo Wang1,2, Fangmin Chen4
1College of Medicine, Nankai University, Tianjin, China.
Background:
Pyroptosis is an inflammatory form of programmed cell death that may remodel the tumor immune microenvironment and influence clinical outcomes. However, the prognostic value of pyroptosis-related molecular patterns and their translational implications in bladder cancer remain incompletely defined. This study aimed to identify pyroptosis-related molecular subtypes, develop and externally validate a subtype-derived prognostic signature, and explore its associations with immune and therapeutic features in bladder cancer.
Methods:
The Cancer Genome Atlas-bladder cancer cohort (TCGA-BLCA) was used as the development cohort, GSE13507 and GSE31684 as external validation cohorts, and IMvigor210 as an exploratory immunotherapy-treated cohort. Pyroptosis-related molecular subtypes were identified by non-negative matrix factorization (NMF), and pathway activity and immune infiltration were assessed by gene set variation analysis (GSVA) and single-sample gene set enrichment analysis (ssGSEA). A subtype-derived six-gene prognostic signature was developed using least absolute shrinkage and selection operator Cox (LASSO-Cox) regression, and performance was evaluated by Kaplan-Meier analysis, time-dependent receiver operating characteristic (ROC) curves, and calibration.
Results:
Two pyroptosis-related molecular subtypes (C1/C2) with distinct survival and immune characteristics were identified. A subtype-derived six-gene prognostic signature comprising ECM1, FER1L4, FKBP10, ANXA1, ARL4C, and CTSE stratified patients into high- and low-risk groups in the development and validation cohorts and remained significantly associated with overall survival (OS) after multivariable adjustment in the TCGA-BLCA cohort. Higher risk scores were associated with higher pathological grade and advanced T stage. Risk stratification was also associated with mutational profiles, immune checkpoint expression, and immunophenoscore (IPS) differences, while CellMiner analysis generated exploratory drug-sensitivity clues.
Conclusions:
We established pyroptosis-related molecular subtypes and developed a subtype-derived six-gene prognostic signature that was evaluated across multiple independent cohorts. The model is associated with immune microenvironment features and genomic context, and offers translational clues for immunotherapy and targeted strategies, warranting further prospective and experimental validation.
