EUO Collaborative Review – Priority Article
Editorial by Rohit K. Jain, Jeffery S. Ross, Andrea Necchi and Philippe E. Spiess on pp. 180–181 of this issue
Genetic Differences Between Bladder and Upper Urinary Tract Carcinoma: Implications for Therapy

https://doi.org/10.1016/j.euo.2020.12.007Get rights and content

Abstract

Context

Bladder urothelial carcinoma (BUC) and upper tract urothelial carcinoma (UTUC) have genetic differences, which may influence therapy.

Objective

The aim of the current review was to summarize the current genetic understanding of upper tract and BUC.

Evidence acquisition

PubMed, Cochrane, and Web of Science online databases were searched systematically up to February 2020, using the following keywords: urothelial carcinomas, upper urinary tract, renal pelvis, ureter, bladder cancer, and genetics.

Evidence synthesis

UTUC and BUC share mutations in similar genes, such as FGFR3, TP53, and HRAS, and epigenetic genes, such as KDM6A and KMT2A-C, but at varying frequencies. Furthermore, subtyping of UTUC and BUC has identified similar expression subtypes, but UTUC is more often luminal with more T-cell depletion. Clonal studies indicate that BUC after UTUC is also likely luminal, while UTUC after BUC is often basal.

Conclusions

UTUC and BUC share many genomic alterations, but at different frequencies, which recapitulate with their metachronous recurrences. These differences likely contribute to the behavior of these two cancers and imply that they and their metachronous recurrences should be treated as two related yet distinct entities.

Patient summary

Urothelial carcinoma of the bladder has distinct genomic features, which are different from distinct genomic features of urothelial carcinoma of the renal pelvis and/or ureter. These features can be used for tailored treatment options specific to tumors of different locations.

Introduction

Urothelial carcinoma (UC), which encompasses disease of the bladder (90–95%) and renal pelvis/ureter (ie, upper tract urothelial carcinoma [UTUC]; 5–10%), is the sixth most common cancer in the USA [1], [2]. Historically, these two diseases have been grouped together because of their histologically similar appearance. Clinically, UTUC and bladder carcinoma have different embryologic precursors and have different responses to therapy, leading many to believe that they should be considered as distinct entities [3]. Recent advancements in technology have led to a better genomic understanding of both bladder cancer and UTUC. Comparisons between tumor mutational burden (TMB) and expression profiles between bladder cancer and UTUC have now shed light on the genomic differences between the two entities [4], [5], [6], [7], [8]. Understanding these differences will be very important for future therapeutic considerations, especially in clinical trial design.

Section snippets

Evidence acquisition

Eligible articles were identified through searches of the electronic databases, Cochrane and Web of Science. English-language articles published between January 2000 and February 2020 were identified and included. The keywords used in the search included the following: urothelial carcinomas, upper urinary tract, renal pelvis, ureter, bladder cancer, and genetics. Additional informative articles were collected by cross-referencing the bibliography of previously selected articles. The article

Genetic alterations in UTUC

The first mutational analysis of UTUC was from a targeted whole-exome analysis of 83 tumor samples from the Memorial Sloan Kettering Cancer Center (MSKCC) with a more recent updated analysis of 195 UTUC tumors [6], [9]. The most frequently mutated genes were FGFR3 (40%), KMT2D (37%), KDM6A (32%), TP53 (26%), and ARID1A (23%) [9]. Most FGFR3 mutations were missense (putative driver) mutations, while KTMT2D, KDM6A TP53, and ARID1A were truncating or missense (putative passenger) mutations [9]. In

Conclusions

The improved genomic understanding of bladder UC and UTUC has shed light onto novel pathways for therapeutic targeting. Furthermore, it has allowed for the ability to identify biomarkers for response. While bladder cancer and UTUC share similarities, to improve treatment outcomes, we need to better functionalize genomics into therapeutics; while this has not yet occurred, we appear to be on the cusp of such.


Author contributions: John P. Sfakianos had full access to all the data in the study and

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