PDF(Pubmed)
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 andRESULTS: 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.
CONCLUSIONS: Distinct genomic and immune landscapes for the four investigated WNT5A pathway components were observed in patients with UC. External validation studies are needed.
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
CONCLUSIONS: Distinct genomic and immune landscapes for the four investigated WNT5A pathway components were observed in patients with UC. External validation studies are needed.
摘要：
背景：通过ROR1及其伴侣通过WNT5A进行的非规范WNT家族（WNT5A通路）信号传导，ROR2或Frizzled2（FZD2）与驱动肿瘤发生和治疗抵抗的过程有关。我们利用大量的尿路上皮癌（UC）肿瘤数据集来表征通过WNT5A的非规范WNT信号，ROR1、ROR2或FZD2表达。
方法：NextGen对提交给CarisLifeSciences的4125个UC肿瘤进行DNA（592个基因或WES）/RNA（WTS）测序。WNT5A的高表达和低表达，ROR1，ROR2和FZD2被定义为≥上四分位数和<下四分位数/百万（TPM），分别。分析基因表达谱的转录特征,预测对免疫疗法的反应。在适当的情况下应用了Mann-WhitneyU和X2/Fisher精确检验，P值调整为多重比较（p<0.05）。从保险索赔数据获得真实世界总生存期(OS)。
结果：WNT5A途径基因表达在原发与转移部位之间差异显著：WNT5A（25.2与16.8TPM)，FZD2（3.2vs.4.05),ROR1（1.7vs.2.1),和ROR2（2.4与2.6)全部p<0.05。高表达和低表达亚组的比较显示TP53、FGFR3和RB1致病性突变的患病率存在差异。以及随着靶基因表达的增加，T细胞发炎的评分也增加。ROR2(HR1.31,95%CI1.15-1.50,p<0.001)和FZD2(HR1.16,95%CI1.02-1.32,p=0.024)的高基因表达与OS恶化相关。
结论：在UC患者中观察到四种WNT5A通路成分的不同基因组和免疫景观。需要进行外部验证研究。
方法：NextGen对提交给CarisLifeSciences的4125个UC肿瘤进行DNA（592个基因或WES）/RNA（WTS）测序。WNT5A的高表达和低表达，ROR1，ROR2和FZD2被定义为≥上四分位数和<下四分位数/百万（TPM），分别。分析基因表达谱的转录特征,预测对免疫疗法的反应。在适当的情况下应用了Mann-WhitneyU和X2/Fisher精确检验，P值调整为多重比较（p<0.05）。从保险索赔数据获得真实世界总生存期(OS)。
结果：WNT5A途径基因表达在原发与转移部位之间差异显著：WNT5A（25.2与16.8TPM)，FZD2（3.2vs.4.05),ROR1（1.7vs.2.1),和ROR2（2.4与2.6)全部p<0.05。高表达和低表达亚组的比较显示TP53、FGFR3和RB1致病性突变的患病率存在差异。以及随着靶基因表达的增加，T细胞发炎的评分也增加。ROR2(HR1.31,95%CI1.15-1.50,p<0.001)和FZD2(HR1.16,95%CI1.02-1.32,p=0.024)的高基因表达与OS恶化相关。
结论：在UC患者中观察到四种WNT5A通路成分的不同基因组和免疫景观。需要进行外部验证研究。
