TERT啟動子突變與GATA3、CK20、CK5/6及p53之表現於膀胱泌尿上皮腫瘤之生物學意義

Abstract

Clinical management of bladder urothelial neoplasm depends mainly on the tumor stage and grade. Recent advances in molecular pathology discovered several essential biomarkers, and their value in clinical application warrants investigation. In our study, we focused on the relevant biomarkers in two separate fields of bladder tumors: the early low-grade noninvasive papillary urothelial neoplasm, and the advanced muscle-invasive bladder cancer (MIBC). In the first part, we investigated the mutation status of the TERT promoter, FGFR3 gene, and HRAS gene in low-grade papillary urothelial neoplasms and evaluated their prognostic significance. Mutations in the promoter region of the TERT gene have been frequently found in urothelial carcinoma of the urinary bladder, but related data for papillary urothelial neoplasm of low malignant potential (PUNLMP) are limited. In our study, we included 21 cases of inverted papillomas, 30 PUNLMPs, and 34 low-grade noninvasive papillary urothelial carcinomas (NIPUCs). TERT promoter mutations were observed in 10 (33%) PUNLMPs and 17 (50%) low-grade NIPUCs, but not in any inverted papilloma. FGFR3 mutations were more frequently observed in PUNLMP and low-grade NIPUC than in inverted papillomas (p = 0.009), whereas the opposite trend was noted for HRAS mutations (p < 0.001). Regarding the clinical outcome, TERT promoter mutation was associated with a higher recurrence rate in PUNLMP (p = 0.024) but not in low-grade NIPUC (p = 0.530). Notably, PUNLMP cases with TERT promoter mutations had a similar recurrence rate to that in low-grade NIPUC cases (p = 0.487). Our results suggest that the status of the TERT promoter mutation may serve as a biomarker of prognostic stratification in patients with PUNLMP. In the second part, we investigated the biological and prognostic significance of GATA3, cytokeratin (CK) 20, CK5/6 and p53 in MIBCs from 91 patients who underwent radical cystectomy. Genetic profiling studies on muscle-invasive bladder cancers (MIBCs) have discovered several subtypes with different biological characteristics, and these markers were found to be associated with the molecular subtypes. According to our results, high Ki-67 indices were associated with negative CK20 (p = 0.002) and diffuse CK5/6 (p = 0.001) staining. By contrast, tumors with diffuse GATA3 expression had low Ki-67 index (p = 0.006). Regarding p53, three staining patterns were associated with a high Ki-67 index: (1) complete absence, (2) diffusely strong nuclear reactivity, and (3) diffusely strong cytoplasmic staining (p < 0.001 compared with other patterns). CK5/6 and CK20 expression was typically present in a reciprocal fashion; however, diffuse GATA3 and CK5/6 coexpression was observed in 13 (14.29%) cases. Among 78 chemotherapy-naive patients, low GATA3 staining was associated with worse recurrence-free survival in both univariate (p = 0.008) and multivariate analyses (p = 0.002). CK20, CK5/6, or p53 expressionwas not associated with clinical outcome. Based on our results, IHC staining for GATA3 may help risk stratification in patients with MIBC receiving radical cystectomy. In addition, the differences in Ki-67 indices suggested that aberrant p53 expression was better defined by the three aforementioned patterns, rather than percentage of nuclear staining alone.