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

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 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.