Upper tract urothelial carcinoma (UTUC) comprises 5% to 10% of urothelial malignancies but demonstrates unique clinical and molecular characteristics compared to urothelial carcinoma of the bladder (UCB). While histologically similar, UTUC and UCB are now considered “disparate twins” based on our increasing knowledge of their biological differences.¹ The advent of next-generation sequencing (NGS) has enabled further molecular characterization of urothelial tumors, with initial efforts focused on bladder tumors and then extrapolated to UTUC.² Urologists must be aware of the clinical implications of UTUC genomics.

Prior work by our group and others used bulk sequencing of tumor tissue to identify the most common somatic DNA alterations present in UTUC, demonstrating a high incidence of potentially actionable genomic alterations including FGFR3 (48%), KDM6A (38%), KMT2D (26%), TERT (26%), TP53 (25%), ARID1A (20%), PIK3CA (16%), TSC1 (14%), HRAS (12%) and ERBB (9%; fig. 1).^3,4 Higher stage (pT2) UTUC was associated with more frequent activating alterations in TP53 and MDM2, while lower stage disease was characterized by more frequent FGFR3 and HRAS alterations.⁵ Whole transcriptome RNA expression analysis of a subset of these tumors demonstrated that 82.5% possessed a luminal-papillary molecular phenotype based on the consensus classifier developed by the Bladder Cancer Molecular Taxonomy Group.³

Figure 1. Somatic genomic landscape of UTUC tumors, stratified by RNA molecular subtypes.³

When compared to UCB, the overall spectrum of somatic alterations is similar, but there are notable differences with significantly more frequent alterations in FGFR3 and HRAS in UTUC, vs TP53, RB1 and ERBB2 in UCB (fig. 2). Intravesical recurrence is relatively common in UTUC, with 22% to 47% of patients developing a bladder tumor.⁶ Our group investigated this relationship further in 29 matched pairs of UTUC and UCB tumors, finding that alterations in FGFR3, KDM6A, CCND1 and TP53 were associated with an increased risk of recurrence and that all pairs were deemed to have a shared clonal origin, suggesting drop-down intravesical seeding.⁵ This finding emphasizes the importance of limiting the risk of lower tract seeding with such steps as early clipping of the ureter during nephroureterectomy, evidence-based use of intravesical chemotherapy, and judicious use of ureteroscopy and postoperative stenting.

Figure 2. Genomic differences between UTUC and UCB.⁵

While sporadic UTUC is much more common, UTUC is known to be associated with Lynch syndrome, a hereditary cancer syndrome characterized by germline mutations in mismatch-repair (MMR) associated genes which results in tumors with microsatellite instability (MSI) and hypermutation.⁷ Lynch-associated UTUC tumors may account for up to approximately 20% of all newly diagnosed UTUC and, without targeted testing, many tumors may be misclassified as sporadic.⁸ UTUC tumors in Lynch patients demonstrate a higher tumor mutational burden (TMB) compared to sporadic UTUC, even those with MMR alterations. This can have profound treatment implications as MSI tumors with high TMB demonstrate better response to immunotherapy.⁹ National Comprehensive Cancer Network® guidelines currently recommend germline DNA testing be considered for all UTUC patients younger than 60 at presentation or with a family history of colon/endometrial cancer.¹⁰ However, given the implications and published age ranges of newly diagnosed cases, our institution and others advocate for broader testing of all UTUC patients to promote increased detection of occult Lynch syndrome prompting appropriate counseling, screening and testing.

While sequencing of tumor tissue provides clinically relevant information, characterization of the tumor immune microenvironment provides additional insight into tumor biology and behavior. Using bulk RNA sequencing, Robinson et al demonstrated that 28 of 32 UTUC tumors analyzed had a T-cell depleted phenotype. Notably, this immune phenotype was associated with upregulated FGFR3 signaling, suggesting a central role of this pathway in shaping the UTUC immune contexture and a potential therapeutic target with targeted agents such as erdafitinib.¹¹

However, bulk genomic characterization of UTUC has some limitations due to intratumoral and temporal heterogeneity.³ Sequencing 1 area of the tumor may not adequately represent the remainder of the disease burden. Similarly, biomarker data may be influenced by sampling techniques and prior therapy. To overcome these limitations, there is increasing interest in single-cell and spatial multi-omics paired with computational methods to more comprehensively characterize these tumors and their immune microenvironment with the goal of better characterizing tumor immune biology and identifying reliable and predictive biomarkers.

Our understanding of the genomics of UTUC will continue to grow with widespread molecular profiling and collaborative research. Increasing clinical utilization of genomic profiling for UTUC will facilitate better screening for hereditary disease, identifying candidates for systemic therapies, and hopefully increasing the ability to provide kidney-sparing treatments to a select group of patients. As urologists, understanding these clinical implications is paramount as we strive to provide the best care for these complex patients.