Abstract 4401: UCHL1 as a potential therapeutic target in uterine papillary serous carcinoma.

Abstract

Abstract Uterine papillary serous carcinoma (UPSC) comprises less than 10% of all endometrial cancers but accounts for a disproportionately high number of deaths. Due to its rarity, few prospective studies have been conducted which focus on this aggressive subtype, and it has been difficult to establish optimal treatment strategies. With poor survival rates and high recurrence rates, the identification of novel therapeutic targets would aid in the management of UPSCs. RNAseq data from The Cancer Genome Atlas (TCGA) was analyzed using Significant Analysis of Microarrays to identify genes that were differentially expressed between 81 cases of grade 2 endometrioid endometrial carcinoma (EEC) and 41 cases of UPSC. A gene of interest was then selected based on its subcellular location, correlation with survival and normal tissue specificity. The findings were validated by immunohistochemical staining of UPSC paraffin sections. All patient samples were obtained and stored in accordance with human subject research protocols approved by the Institutional Review Board. All paraffin sections were reviewed by a pathologist. By comparing the RNAseq profiles of UPSCs and EECs, we identified 242 genes that were differentially expressed (q<0.005). Among these, ubiquitin C-terminal hydrolase 1 (UCHL1) showed higher expression in UPSCs compared to EECs, with an increase of over 6-fold. UCHL1 was chosen for further studies as Kaplan-Meier analysis of all endometrial cases in the TCGA database revealed that UCHL1 expression also correlated significantly with poorer disease-free survival (p<0.05). Preliminary immunohistochemical studies also show higher expression of UCHL1 in UPSCs than in ECCs. Interestingly, contrast analysis of TCGA data for breast cancer indicates that basal-like breast tumors also show significantly higher UCHL1 expression compared to the other breast cancer subtypes (p<0.005). Both basal-like breast cancer and UPSC have a high rate of p53 mutation (80% and 90%); this shared upregulation of UCHL1 suggests that a possible mechanism by which UCHL1 contributes to pathogenesis is through stabilization of mutant p53. In conclusion, our data identifies UCHL1 as a gene that is upregulated in UPSCs and is associated with poor disease-free survival. UCHL1 is a possible novel therapeutic target for the management of UPSCs. Further studies are needed to elucidate the underlying mechanisms in which it contributes to tumorigenesis. Citation Format: Suet Ying Kwan, Kwong-Kwok Wong, Rosemarie E. Schmandt, Karen H. Lu. UCHL1 as a potential therapeutic target in uterine papillary serous carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4401. doi:10.1158/1538-7445.AM2013-4401