Introduction

In urothelial carcinoma, genetic alterations in multiple cell-cycle regulations genes are frequent, including key tumor suppressor genes like TP53 and RB1. Prior studies have shown that alterations of TP53 and RB1, analyzed through protein p53 and RB expression respectively have prognostic significance. The goal of this study was to evaluate the correlation between TP53 and RB1 genotypes and phenotypes._x000D_

Methods

Tumor and matched germline DNA were analyzed using the MSK-IMPACT assay that detects alterations in 410 oncogenes and tumor suppressor genes, including TP53 and RB1. A correlation between TP53 and RB1 mutation status and protein expression was performed. Tissue microarrays (TMA) of urothelial carcinoma of the bladder were assessed for p53 and RB expression as a validation cohort. _x000D_

Results

Overall, 171 patients with a median age of 69.4 years (IQR: 61.7-71.5) were included. Clinical stage was non muscle invasive bladder cancer in 14 (8.2%) patients, muscle invasive bladder cancer in 148 (86.5%) and metastatic in 9 (5.3%). Genetic alterations of TP53 and RB1 were found in 93 (53.8%) and 66 (38.2%) patients respectively. Protein expression was assessed from full section in 65 (38%) patients and from TMA in 106 (62%). Strong and diffuse p53 expression strongly correlated with missense TP53 mutations (n=43, 78.2%, p<0.0001). In addition, complete lack of p53 expression was seen in tumors harboring truncating TP53 mutations (n= 20, 58.8%, p<0.0001). Similarly, loss of RB expression strongly correlated with the presence of RB1 mutations (n=43, 86%, p<0.0001). Tumors with wildtype TP53 or RB exhibited variable p53 and RB expression. In cases with both invasive and non-invasive components (n=24), similar patterns of p53 and RB expression were observed._x000D_

Conclusions

The most common pattern of p53 expression that correlated with the presence of TP53 mutations are strong and diffuse nuclear expression (missense mutation) and absence of nuclear expression (truncating mutation). RB1 mutations generally result in loss of RB expression. The concordant pattern of p53 and RB expression between invasive and non-invasive component within the same tumor indicate that alterations in these genes occur early in the development of urothelial carcinoma._x000D_

Funding

None