Transcriptomic Profiling of Upper Tract Urothelial Carcinoma: Bladder Cancer Consensus Classification Relevance,
Jacqueline Fontugne1, Evanguelos Xylinas2, Clémentine Krucker3
1Department of Pathology, Institut Curie, Saint-Cloud, France; Institut Curie, CNRS, UMR144, Equipe labellisée Ligue Contre le Cancer, Paris Sciences et Lettres Research University, Paris, France; Université Paris-Saclay, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
Summary
The consensus classification for muscle-invasive bladder cancer (MIBC) effectively categorizes upper tract urothelial carcinomas (UTUCs), revealing a higher proportion of luminal papillary (LumP) subtypes in UTUCs. LumP UTUCs often exhibit low immune infiltration and high FGFR3 mutation rates, suggesting different treatment responses compared to MIBC.
Area of Science:
- Oncology
- Genomics
- Molecular Pathology
Background:
- Muscle-invasive bladder cancer (MIBC) has a consensus molecular classification, but upper tract urothelial carcinomas (UTUCs) remain less understood.
- Characterizing UTUC molecular subtypes is crucial for understanding disease behavior and guiding treatment strategies.
Purpose of the Study:
- To determine the relevance of the MIBC consensus classification in UTUCs.
- To characterize molecular subtypes and intratumoral heterogeneity in a cohort of surgically treated UTUCs (≥pT1).
Main Methods:
- Immunohistochemistry (IHC) for subtype markers, p16, Ki67, mismatch repair proteins, and PD-L1.
- FGFR3 mutation analysis by pyrosequencing and 3'RNA sequencing.
- Gene expression analysis for consensus classes, unsupervised groups, and microenvironment cell abundance.
Main Results:
- The MIBC consensus classification robustly classified UTUCs, with luminal papillary (LumP) being the predominant subtype, especially in ≥pT2 tumors (57.2%).
- FGFR3 mutations were found in 40% of UTUCs; LumP tumors frequently harbored these mutations and showed low immune infiltration and PD-L1 expression.
- Intratumoral heterogeneity was observed in 15.2% of cases, with consensus classes correlating with FGFR3 mutations, stage, morphology, and IHC markers.
Conclusions:
- The MIBC consensus classification is applicable to UTUCs, highlighting a higher prevalence of LumP subtypes compared to MIBC.
- LumP UTUCs, particularly those with FGFR3 mutations, are characterized by low immune infiltration and PD-L1 expression.
- These molecular differences suggest that UTUCs may respond differently to novel therapies compared to MIBC.
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