李威明^1,2,3、吳文正^1,3、李經家^1,3、柯宏龍^1,3、韋又菁⁵、葉信志^1,3,4、李香瑩^3,4

李健逢⁶、黃俊農^3,4、黃俊雄^1,3

高雄醫學大學附設中和紀念醫院泌尿部¹; 衛生福利部屏東醫院泌尿科²; 高雄醫學大學醫學系泌尿學科³; 高雄市立大同醫院泌尿科⁴; 高雄市立大同醫院病理科⁵; 奇美醫學中心病理部⁶

Wei-Ming Li ^1,2,3, Wen-Jeng Wu ^1,3, Ching-Chia Li ^1,3, Hung-Lung Ke ^1,3, Yu-Ching Wei⁵, Hsin-Chin Yen^1,3,4, Hsiang-Ying Lee^3,4, Chien-Feng Li⁶, Chun-Nung Huang ^3,4, Chun-Hsiung Huang ^1,3

¹Department of Urology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

² Department of Urology, Pingtung Hospital, Ministry of Health and Welfare, Executive Yuan, Pingtung, Taiwan

³ Department of Urology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

⁴ Department of Urology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

⁵ Department of Pathology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan

⁶Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan

 

Purpose: Urothelial carcinomas (UC) of urinary bladder (UB) and upper urinary tract (UT) are heterogeneous diseases with high morbidity and mortality. The molecular pathogenesis of UC has not been fully elucidated. We looked for genes with metal ion binding in a published UBUC transcriptomic database (GSE32894): Metallothionein 2A (MT2A) was the most significant gene, showing stepwise up-regulation. We analyzed MT2A expression and association with clinicopathologic factors and

survival in our well-characterized cohort of UCs.

Materials and Methods: We determined MT2A expression in 340 upper urinary tract UCs (UTUC)and 295 urinary bladder UCs (UBUC) using immunohistochemistry and evaluated the results using H-score. MT2A expression correlated with clinicopathological features, disease-specific survival (DSS), and metastasis-free survival (MFS). Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards model.

Results: High MT2A expression was significantly associated with advanced pT status, nodal metastasis, high histological grade, vascular and perineural invasion (PNI). High MT2A expression was significantly associated with worse DSS (P<0.0001) and MFS. In UTUC, after adjusting all significant predictors in univariate analysis, MT2A expression remained an independent predictor of DSS (hazard ratio [HR]:6.248, 95% confidence interval [CI]:2.424-16.106; P<0.001) and MFS (HR:2.973, 95% CI: 1.537-5.754; P=0.001) in multivariate Cox regression analysis. In UBUC, multivariate analysis additionally demonstrated that pathological stage, PNI, mitotic rate, and MT2A expression status (HR: 2.114, 95% CI:1.132-3.946; P=0.019) significantly correlated with DSS; pathological stage, mitotic rate, and MT2A expression status (HR:3.648, 95% CI:2.052-4.683; P<0.001) were considerably associated with MFS

Conclusions: MT2A overexpression was associated with unfavorable clinicopathological characteristics and independent negative prognostic effects, justifying its potential theranostic value in UC.