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

Q: What did the study measure in UUTUC patients?

The study assessed ACTN4 protein expression and ACTN4 gene copy number gain using immunohistochemistry and fluorescence in situ hybridization (FISH).

Q: How were ACTN4 copy number gain and protein overexpression related?

ACTN4 copy number gain detected by FISH significantly correlated with ACTN4 protein overexpression and multiple adverse clinicopathological factors.

Q: Which ACTN4 finding independently predicted worse outcomes?

Multivariate analysis indicated that ACTN4 copy number gain was the independent risk factor for extraurothelial recurrence and death.

Sep 24, 2026

Uploaded by Riley West

α-Actinin4 (ACTN4), a non-muscular α-actinin isoform that promotes cancer infiltration and metastasis, shows insufficiently characterized pathological significance in upper urinary tract urothelial carcinomas (UUTUCs). Tumor samples from 168 newly diagnosed UUTUC patients (renal pelvis, n=92; ureter, n=76) treated by nephroureterectomy or partial ureterectomy were analyzed for ACTN4 protein expression and ACTN4 copy number gain by immunohistochemistry and FISH. Median follow-up was 65 months.

LanguageEnglish

CategoryHealthcare

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Pages12

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Abstract

Study design and cohort

ACTN4 protein overexpression and copy number gain

Clinicopathological correlations

Prognostic analysis and key finding

DOI: 10. 1111/cas.15841 OR I G I NAL ART I C L E Copy number gain of ACTN4 is associated with poor prognosis in patients with upper urinary tract urothelial carcinoma Kazuki Kawamura1,2 | Kosuke Miyai2,3 | Kimiya Sato2 | Susumu Matsukuma3 | Kazufumi Honda4 | Keiichi Ito1 | Hitoshi Tsuda2 1Department of Urology, National Defense Medical College, Tokorozawa, Japan 2Department of Basic Pathology, National Defense Medical College, Tokorozawa, Japan 3 Department of Laboratory Medicine, National Defense Medical College, Tokorozawa, Japan 4Department of Bioregulation, Graduate School of Medicine, Nippon Medical School, Bunkyo-ku, Japan Correspondence Kosuke Miyai, Department of Basic Pathology, National Defense Medical College, 3–2 Namiki, Tokorozawa, Saitama 359–8513, Japan. [Email:](Email: mykusu228@nifty.com)[ mykusu228@nifty.com](Email: mykusu228@nifty.com) Abstract 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. K E Y WO R D S epithelial–mesenchymal transition, fluorescence in situ hybridization, upper urinary tract, urothelial carcinoma, α-actinin4 Abbreviations: ACTN4, α-actinin4; CIS, carcinoma in situ; EMT, epithelial–mesenchymal transition; FISH, fluorescence in situ hybridization; LVI, lymphovascular invasion; pT stage, pathological T stage; UTUC, urinary tract urothelial carcinoma; UUTUC, upper urinary tract urothelial carcinoma; WHO, World Health Organization. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. 1 | INTRODUCTION UUTUC accounts for ~5% of all UTUCs.1 Various clinicopathological parameters, such as pT stage, tumor grade, and LVI, have been recognized as important prognostic factors of UUTUC.1 However, there are some issues regarding the clinical implications of these conventional clinicopathological parameters, such as heterogeneous clinical behavior of pT3 renal pelvic cancer depending on the degree of renal parenchymal invasion2,

FAQs

What did the study measure in UUTUC patients?

The study assessed ACTN4 protein expression and ACTN4 gene copy number gain using immunohistochemistry and fluorescence in situ hybridization (FISH).

How were ACTN4 copy number gain and protein overexpression related?

ACTN4 copy number gain detected by FISH significantly correlated with ACTN4 protein overexpression and multiple adverse clinicopathological factors.

Which ACTN4 finding independently predicted worse outcomes?

Multivariate analysis indicated that ACTN4 copy number gain was the independent risk factor for extraurothelial recurrence and death.

Sep 24, 2026

Uploaded by Riley West