Copy number gain of ACTN4 is associated with poor prognosis in patients with upper urinary tract urothelial carcinoma

α‐Actinin4 (ACTN4), an isoform of non‐muscular α‐actinin, is involved in enhancing cell motility and promoting cancer infiltration and metastasis in various cancers. However, information remains limited regarding the pathological significance of ACTN4 expression in upper urinary tract urothelial carcinomas (UUTUCs). We obtained tumor samples from 168 consecutive patients with newly diagnosed UUTUCs (92 with renal pelvic cancers and 76 with ureteral cancers), who were treated with nephroureterectomy or partial ureterectomy, and analyzed the expression of the ACTN4 protein and the amplification of ACTN4 using immunohistochemistry and fluorescence in situ hybridization (FISH), respectively. The median follow‐up duration was 65 months. Among 168 cases, 49 (29%) showed ACTN4 protein overexpression and 25 (15%) showed copy number gain (≥4 copies per cell) of ACTN4. The copy number gain of ACTN4 detected using FISH significantly correlated with ACTN4 protein overexpression and several adverse clinicopathological factors, including higher pathological T stage, lymphovascular invasion, lymph node metastasis, positive surgical margin, concomitant subtype histology, and non‐papillary gross finding. Cox univariate regression analyses revealed that both copy number gain of ACTN4 and ACTN4 protein overexpression were significant risk factors for extraurothelial recurrence and death (each p < 0.0001), but multivariate analysis revealed that only copy number gain of ACTN4 was an independent risk factor for extraurothelial recurrence and death (p = 0.038 and 0.027, hazard ratio = 2.16 and 2.17, respectively). This is the first study demonstrating the aberrant expression status of ACTN4 in UUTUC and indicating its putative usefulness as a prognostic indicator in patients with UUTUC.