Development and validation of an intra-tumor heterogeneity-related signature to predict prognosis of bladder cancer: a study based on single-cell RNA-seq.

Ranran Zhou,Cundong Liu,Cheng Yang,Hu Tian,Qi Chen,Jingjing Liang

doi:10.18632/aging.203353

Abstract

Intra-tumor heterogeneity (ITH) was a potential mechanism of progression and drug resistance in bladder cancer (BCa). However, the understanding of ITH in BCa remains insufficient. Single-cell RNA sequencing (scRNA-seq) profiles of 2075 cells were analyzed, and 2940 cell markers were screened. The ITH of 396 cases was evaluated, and 96 ITH-related genes were identified. Based on the gene-pair strategy, 96 genes were cyclically paired, and an 8-gene-pair model was successfully established to evaluate the overall survival of BCa through Lasso and multivariate Cox regressions. The risk model showed high predictive value in the training dataset (n = 396, p = 0) and external validation datasets (n = 165, p = 2.497e-02; n = 224, p = 3.423e-02). The model was also valuable for the prediction of clinical treatment outcomes. Totally, a prognostic model based on scRNA-seq and ITH was successfully constructed and validated in large cohorts, providing novel clues for ITH study of BCa.

Highlights

Bladder cancer (BCa), as the twelfth most common malignancies around the world, brings a tremendous social burden [1]
The intra-tumor heterogeneity (ITH) of each individual was quantified as mutant-allele tumor heterogeneity (MATH) value, and high MATH represented increased ITH of malignant tumors [13]
It was found that the BCa cases with high MATH suffered a poorer survival rate (p = 4.146e-02, Figure 1B) and lower sensitivity to chemotherapeutic agents (Figure 1C)

Summary

Introduction

Bladder cancer (BCa), as the twelfth most common malignancies around the world, brings a tremendous social burden [1]. The 5-year survival rate of muscleinvasive bladder cancer (MIBC), one of the main subtypes of BCa, is dismal: 5%–30% [2]. Some novel therapeutic methods, such as cisplatin-based neoadjuvant chemotherapy and immune checkpoint inhibitors (ICIs), have been proposed, making considerable strides in BCa treatment [3]. Many BCa patients could not benefit from the current therapeutic regimens [4, 5]. Reliable prediction of prognosis was urgently demanded, which played an important role in guiding clinical treatment. ITH is capable of predicting the prognosis of patients with malignancies [8]. The underlying mechanisms of ITH include telomere damage, DNA mismatch repair deficiency, microsatellite instability (MSI), and epigenetic changes [9], but the understanding of ITH is far from enough for the moment

Methods

Results

Conclusion