Traditional Classification and Novel Subtyping Systems for Bladder Cancer

Abstract

Bladder cancer is the most common tumor in the urinary system, with approximately 420,000 new cases and 160,000 deaths per year. The European Organization for Research and Treatment of Cancer (EOTRC) classifies non-muscular invasive bladder cancer (NMIBC) into low-risk, medium-risk and high-risk groups based on a comprehensive analysis of NMIBC pathological parameters and the risk of recurrence and progression to muscular invasive bladder cancer (MIBC). Traditional classification systems are based on pathologic grading, staging systems, and clinical prognosis. However, the pathological parameters of the tumor cannot fully reflect the "intrinsic characteristics" of bladder cancer, and tumors with a similar pathology exhibit different biological behaviors. Furthermore, although the traditional classification system cannot accurately predict the risk of recurrence or the progression of bladder cancer patients (BCs) individually, this method is widely used in clinical practice because of its convenient operation. With the development of sequencing and other technologies, the genetics-based molecular subtyping of bladder cancer has become increasingly studied. Compared with the traditional classification system, it provides more abundant tumor biological information and is expected to assist or even replace the traditional typing system in the future.

Keywords: EOTRC; bladder cancer; clinical prognosis; molecular subtypes; multiomics.

Figure 1

BC molecular subtyping systems. BC, bladder cancer; NMIBC, non-muscular invasive bladder cancer; MIBC muscular invasive bladder cancer.

Figure 2

Heatmap of mRNA-seq data from the Lun 2012 molecular subtyping system. BCs are divided into five subtypes according to their genetic expression profiles (32). Red, high expression; green, low expression; black; mutation; white, wild-type; gray, no mutation data. SSC, squamous cell carcinoma; FGFR3, fibroblast growth factor receptor 3.

Figure 3

The correlation among UROMOL 2016 and other molecular subtyping systems (33). (A) The UROMOL 2016 subytping system analyzed the microarray data from 306 tumors from the Lund group based on 95 of 117 classifier genes (33). The Class 1 subtype is highly similar to the urobasal A subtype, and Class 1 subtypes mainly consist of low-risk NMIBC, while high-risk NMIBC tends to be concentrated in the Class 3 and Class 2 subtypes. (B) UROMOL 2016 was used to subtype the TCGA database (33). Heatmap of mRNA-seq data from 408 MIBC samples from TCGA based on 107 of the 117 classifier genes. Class 1 and Class 2 tumors are highlighted based on expression profile similarities to original classes. Class 2*: tumors with high similarity to Class 2 but with differences in EMT and CSC marker expression (33). Yellow, high expression; blue, low expression. SSC, squamous cell carcinoma; EMT, endothelial-mesenchymal transformation; CSC: cancer stem cell.

Figure 4

Traditional classification and novel subtyping systems for bladder cancer. NMIBC, Non-muscular invasive bladder cancer; BCG, Bacillus Calmette—Guerin; BCs, bladder cancer patients.