Squamous cell carcinoma (SCC) of the bladder is a rare but highly aggressive malignancy associated with poor clinical outcomes and limited responsiveness to conventional therapies. Recently, Professor Guoliang Yang’s team from Renji Hospital, Shanghai Jiao Tong University School of Medicine, together with Professor Xianbin Su’s group from the Institute of Systems Biomedicine at Shanghai Jiao Tong University, published a landmark study in the Journal of Pathology titled “Cellular origins and etiological factors for squamous cell carcinoma and related cancer types of the bladder.”By integrating whole-exome sequencing (WES), bulk RNA sequencing, and single-cell RNA sequencing (scRNA-seq), the investigators performed one of the most comprehensive molecular comparisons to date between pure bladder SCC, urothelial carcinoma (UC) with squamous differentiation, and conventional urothelial carcinoma. The study provides important new insights into tumor biology, molecular evolution, and potential cellular origins.
Background
Bladder cancer is among the most common genitourinary malignancies, with urothelial carcinoma accounting for approximately 90% of cases. In contrast, primary bladder SCC represents only 2%–5% of diagnoses but is typically detected at advanced stages and responds poorly to chemotherapy and radiotherapy.
Although squamous differentiation is frequently observed in urothelial carcinoma, systematic molecular comparisons between pure SCC and squamous-differentiated UC have remained limited.
Shared Mutational Features Suggest Common Early Drivers
The research team performed multi-omics analyses on tumor samples collected from 29 patients.
One of the study’s key findings was the remarkable overlap in driver gene alterations among SCC, squamous-differentiated UC, and pure UC. Frequently altered genes included TP53, KDM6A, and MUC16, with mutations distributed broadly rather than clustered at specific hotspots. These results suggest that the three tumor subtypes may share common early oncogenic events.
The investigators also identified APOBEC-associated mutational signatures (SBS2/SBS13) in approximately one-third of cases, consistent with mutational processes commonly observed during early urothelial carcinoma evolution.
Using their newly developed “ALT-VAF” two-dimensional analytical model, the researchers further demonstrated that high-VAF clonal mutations and low-VAF rare mutations exhibited distinct nucleotide substitution patterns. This finding indicates that different carcinogenic pressures may influence tumor evolution at different stages of disease progression.
Transcriptomic Analysis Reveals Strong Basal/Squamous Identity
At the transcriptomic level, bladder SCC and squamous-differentiated UC displayed highly similar expression profiles.
Both subtypes showed marked upregulation of basal/squamous markers such as KRT5, KRT14, and TP63, while conventional urothelial carcinoma demonstrated stronger expression of luminal markers including KRT20 and GATA3.
Single-cell sequencing further validated these observations. SCC tumor cells consistently maintained strong basal-like transcriptional programs even at the single-cell level. Importantly, metastatic lymph node lesions exhibited expression patterns highly consistent with those of the primary tumors, suggesting stable lineage characteristics during metastatic spread.
Biological Implications
The study highlights an important concept: although bladder SCC and urothelial carcinoma may share overlapping mutational backgrounds, their transcriptomic states are fundamentally different.
This “shared mutations but divergent phenotypes” phenomenon may reflect differences in cellular origin or epigenetic reprogramming during tumor evolution.
According to Professor Guoliang Yang:
“Our findings provide a valuable molecular resource for understanding bladder SCC and related tumor subtypes. Identifying subtype-specific transcriptional features and mutational signatures may not only improve pathological diagnosis, but also support the future development of precision immunotherapies and targeted interventions.”
Clinical Significance
This work represents an important advance in the molecular characterization of rare bladder cancers. By integrating genomic, transcriptomic, and single-cell analyses, the study deepens current understanding of bladder SCC biology and opens new possibilities for:
- precision pathological classification,
- biomarker-guided diagnosis,
- targeted therapeutic development,
- and future immunotherapy strategies.
The findings also reinforce the growing importance of multi-omics approaches in decoding tumor heterogeneity and identifying clinically actionable molecular subtypes in urologic oncology.
Expert Profile
Professor Guoliang Yang Department of Urology Renji Hospital, Shanghai Jiao Tong University School of Medicine
