Characterization and impact of non‐canonical WNT signaling on outcomes of urothelial carcinoma

Abstract

Abstract Background Non‐canonical WNT family (WNT5A pathway) signaling via WNT5A through ROR1 and its partner, ROR2, or Frizzled2 (FZD2) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non‐canonical WNT signaling through WNT5A, ROR1, ROR2, or FZD2 expression. Methods NextGen Sequencing of DNA (592 genes or WES)/RNA (WTS) was performed for 4125 UC tumors submitted to Caris Life Sciences. High and low expression of WNT5A, ROR1, ROR2, and FZD2 was defined as ≥ top and <bottom quartile of transcripts per million (TPM), respectively. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy. Mann–Whitney U and X2/Fisher Exact tests were applied where appropriate, with p‐values adjusted for multiple comparisons (p < 0.05). Real‐world overall survival (OS) was obtained from insurance claims data. Results WNT5A pathway gene expression varied significantly between primary versus metastatic sites: WNT5A (25.2 vs. 16.8 TPM), FZD2 (3.2 vs. 4.05), ROR1 (1.7 vs. 2.1), and ROR2 (2.4 vs. 2.6) p < 0.05 for all. Comparison of high‐ and low‐expression subgroups revealed variation in the prevalence of TP53, FGFR3, and RB1 pathogenic mutations, as well as increasing T cell‐inflamed scores as expression of the target gene increased. High gene expression for ROR2 (HR 1.31, 95% CI 1.15–1.50, p < 0.001) and FZD2 (HR 1.16, 95% CI 1.02–1.32, p = 0.024) was associated with worse OS. Conclusion Distinct genomic and immune landscapes for the four investigated WNT5A pathway components were observed in patients with UC. External validation studies are needed.

Keywords

• FZD2
• Non‐canonical
• ROR
• Urothelial carcinoma
• WNT signaling
• WNT5A