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. Genes altered more commonly in high-grade UTUC included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes less frequently mutated in high-grade UTUC included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and 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.

Keywords: Bladder cancer; Genomics; Targeted therapy; Upper tract urothelial carcinoma.

Fig. 1

Representation of the 14 most frequently altered genes in a series of 82 upper tract urothelial carcinoma tumors. Mutations are categorized as missense mutations reported in COSMIC (green), gene fusions (black triangle), novel missense mutations (gray), truncating nonsense mutations or indels (black), amplifications (red bar), and deletions (blue bar).

Fig. 2. Significant differences in prevalence of mutations identified between the high-grade upper tract urothelial carcinoma (black bars) and high-grade urothelial carcinoma of the bladder (gray bars) cohorts. Mutation frequencies of the Cancer Genome Atlas high-grade bladder cohort (white bars) are displayed for comparison

TCGA = The Cancer Genome Atlas; UCB = urothelial carcinoma of the bladder; UTUC = upper tract urothelial carcinoma.

Fig. 3. Comparison of copy-number alterations in upper tract urothelial carcinoma stratified by pathologic grade, stage, and FGFR3/HRAS and TP53/MDM2 alteration status. Copy-number gains (red) and losses (blue) are quantified in bar graphs at the top

HG = high grade; LG = low grade.

Fig. 4

OncoPrint comparing mutations in FGFR3, HRAS, and TP53 between low-grade and high-grade upper tract urothelial carcinoma. FGFR3 mutations were detected in 22 of 23 low-grade tumors, and a pattern of mutual exclusivity between FGFR3, HRAS and TP53 was seen in the high-grade tumors. Alterations in chromatin-modifying genes were common in both the low-grade and high-grade tumors.