Genomic Characterization of Upper Tract Urothelial Carcinoma

Abstract

Background Despite a similar histologic appearance, upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) tumors have distinct epidemiologic and clinicopathologic differences. Objective To investigate whether the differences between UTUC and UCB result from intrinsic biological diversity. Design, setting, and participants Tumor and germline DNA from patients with UTUC (n = 83) and UCB (n = 102) were analyzed using a custom next-generation sequencing assay to identify somatic mutations and copy-number alterations in 300 cancer-associated genes. Outcome measurements and statistical analysis We described co-mutation patterns and copy-number alterations in UTUC. We also compared mutation frequencies in high-grade UTUC (n = 59) and high-grade UCB (n = 102). Results and limitations Comparison of high-grade UTUC and UCB revealed significant differences in the prevalence of somatic alterations. Alterations more common in high-grade UTUC included fibroblast growth factor receptor 3 (FGFR3; 35.6% vs 21.6%; p = 0.065), Harvey rat sarcoma viral oncogene homolog (HRAS; 13.6% vs 1.0%; p = 0.001), and cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4) (CDKN2B; 15.3% vs 3.9%; p = 0.016). Genes less frequently mutated in high-grade UTUC included tumor protein p53 (TP53; 25.4% vs 57.8%; p < 0.001), retinoblastoma 1 (RB1; 0.0% vs 18.6%; p < 0.001), and AT rich interactive domain 1A (SWI-like) (ARID1A; 13.6% vs 27.5%; p = 0.050). Because our assay was restricted to genomic alterations in a targeted panel, rare mutations and epigenetic changes were not analyzed. Conclusions High-grade UTUC tumors display a spectrum of genetic alterations similar to high-grade UCB. However, there were significant differences in the prevalence of several recurrently mutated genes including HRAS, TP53, and RB1. As relevant targeted inhibitors are being developed and tested, these results may have important implications for the site-specific management of patients with urothelial carcinoma. Patient summary Comparison of next-generation sequencing of upper tract urothelial carcinoma (UTUC) with urothelial bladder cancer identified that similar mutations were present in both cancer types but at different frequencies, indicating a potential need for unique management strategies. UTUC tumors were found to have a high rate of mutations that could be targeted with novel therapies.

Genomic Biomarkers for the Prediction of Stage and Prognosis of Upper Tract Urothelial Carcinoma

“…Targeted capture-based next-generation sequencing (Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets, MSK-IMPACT) to identify somatic mutations and copy number alterations was performed on all specimens (10, 11). Pre-specified genomic alterations deemed to have functional significance were analyzed.…”

“…The genomic landscape of UTUC is less clear. Recently, our group published a comparative genomic analysis of UTUC and bladder UC (10). This work demonstrates that the types of mutations found in invasive bladder and upper tract tumors are similar, but the mutational frequency is quite different.…”

Diagnostic Ureteroscopy Prior to Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma Increased the Risk of Intravesical Recurrence

“…Intraluminal tumor seeding seems like the most possible reason for IVR after URS because Chen et al [29] found that clipping the distal ureter prior to RNU could significantly reduce IVR. However, studies have demonstrated that the UC that occurred in upper tract and bladder had similar genomic characterisation using next-generation sequencing, thus it is much harder to distinguish whether the origin of subsequent IVR was from seeds of UTUC [30]. Regardless, it is now clear that preoperative URS increases the risk of IVR after RNU.…”

Bridging the Gap in Upper Tract Urothelial Carcinoma

“…In this month's issue of European Urology, Sfakianos and colleagues [4] report on the largest targeted next-generation DNA-sequencing study of UTUC. The authors used an exoncapture assay consisting of 300 cancer-associated genes (Memorial Sloan Kettering Cancer Center's IMPACT platform) to compare somatic DNA mutations in a cohort of 59 highgrade UTUCs versus 102 high-grade urothelial cancers of the bladder (UCBs) and in 23 low-grade versus 59 high-grade UTUCs, using either frozen or paraffin-embedded tissues from nephroureterectomy.…”