{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,30]],"date-time":"2025-07-30T08:06:12Z","timestamp":1753862772854,"version":"3.41.2"},"reference-count":26,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T00:00:00Z","timestamp":1711929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Non\u2010canonical WNT family (WNT5A pathway) signaling via <jats:italic>WNT5A<\/jats:italic> through <jats:italic>ROR1<\/jats:italic> and its partner, <jats:italic>ROR2<\/jats:italic>, or Frizzled2 (<jats:italic>FZD2<\/jats:italic>) is linked to processes driving tumorigenesis and therapy resistance. We utilized a large dataset of urothelial carcinoma (UC) tumors to characterize non\u2010canonical WNT signaling through <jats:italic>WNT5A<\/jats:italic>, <jats:italic>ROR1<\/jats:italic>, <jats:italic>ROR2<\/jats:italic>, or <jats:italic>FZD2<\/jats:italic> expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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 <jats:italic>WNT5A<\/jats:italic>, <jats:italic>ROR1<\/jats:italic>, <jats:italic>ROR2<\/jats:italic>, and <jats:italic>FZD2<\/jats:italic> was defined as \u2265 top and &lt;bottom quartile of transcripts per million (TPM), respectively. Gene expression profiles were analyzed for a transcriptional signature predictive of response to immunotherapy. Mann\u2013Whitney <jats:italic>U<\/jats:italic> and X2\/Fisher Exact tests were applied where appropriate, with <jats:italic>p<\/jats:italic>\u2010values adjusted for multiple comparisons (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05). Real\u2010world overall survival (OS) was obtained from insurance claims data.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>WNT5A pathway gene expression varied significantly between primary versus metastatic sites: <jats:italic>WNT5A<\/jats:italic> (25.2 vs. 16.8 TPM), <jats:italic>FZD2<\/jats:italic> (3.2 vs. 4.05), <jats:italic>ROR1<\/jats:italic> (1.7 vs. 2.1), and <jats:italic>ROR2<\/jats:italic> (2.4 vs. 2.6) <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05 for all. Comparison of high\u2010 and low\u2010expression subgroups revealed variation in the prevalence of <jats:italic>TP53<\/jats:italic>, <jats:italic>FGFR3<\/jats:italic>, and <jats:italic>RB1<\/jats:italic> pathogenic mutations, as well as increasing T cell\u2010inflamed scores as expression of the target gene increased. High gene expression for <jats:italic>ROR2<\/jats:italic> (HR 1.31, 95% CI 1.15\u20131.50, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and <jats:italic>FZD2<\/jats:italic> (HR 1.16, 95% CI 1.02\u20131.32, <jats:italic>p<\/jats:italic>\u2009=\u20090.024) was associated with worse OS.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Distinct genomic and immune landscapes for the four investigated WNT5A pathway components were observed in patients with UC. External validation studies are needed.<\/jats:p><\/jats:sec>","DOI":"10.1002\/cam4.7148","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T12:00:58Z","timestamp":1711972858000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Characterization and impact of non\u2010canonical <scp>WNT<\/scp> signaling on outcomes of urothelial carcinoma"],"prefix":"10.1002","volume":"13","author":[{"given":"Margaret","family":"Meagher","sequence":"first","affiliation":[{"name":"Department of Urology UC San Diego School of Medicine  La Jolla California USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3481-8364","authenticated-orcid":false,"given":"Harris","family":"Krause","sequence":"additional","affiliation":[{"name":"Caris Life Sciences  Phoenix Arizona 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