Abstract 106: Transcriptionnal profiling of upper-tumor urothelial carcinomas

Abstract

Abstract Background: Upper-tumor urothelial carcinomas (UTUC) represent 5% among all urothelial tumors. The most frequent histological variant is transitional cell carcinomas (TCC). UTUC might arise within renal pelvis or ureters. Several studies suggested aggressive behavior of tumors arising within the ureter as compared to those which develop within renal pelvis. However, whether there is a biological basis of this difference remains unknown. Methods: We performed RNAsequencing on fourteen UTUC including 6 cases arising in the ureter and 8 in renal pelvis. Library prep followed by next-generation sequencing were done using Illumina Hiseq platform. Unsupervised clustering using differentially expressed genes was used to identify cancer subtypes. Identified subtypes were correlated with clinico-pathological features. Pathway analysis was performed using Gene Set Enrichment Analysis (GSEA). Results: Unsupervised clustering of gene expression revealed two clusters. Surprisingly, all tumors (n = 5/5) encompassing C1 were located in the ureters as compared to only one (n = 1/9) in C2 cluster (p = 0.003). No difference was observed between C1 and C2 clusters according to age, gender, grade, muscle-invasion status and stage. Using stringer cut-off (fold change ≥ or ≤-2 and FDR<0.05), 34 genes were found to be differentially expressed between the 2 clusters. GSEA revealed negative enrichment of several pathways related to B and T-cell activation in C1 relative to C2 cluster. This was the case for NAIVE_TCELL_VS_DC_UP (p = 0.01; FDR = 0.16) and NAIVE_BCELL_VS_NEUTROPHIL_UP (p = 0.002; FDR = 0.12). Among the most overexpressed genes in C1 cluster, we identified the serine/threonine-protein kinase gene SGK2 (Fold change = 17; FDR = 0.004) as a putative therapeutic target. Of note, AIM2 which is part of the inflammasome with a key role in tumorigenic reversion was one of the most down-regulated genes (fold change = -24; FDR = 0.02) in C1 cluster. Conclusion: Our report suggests that transcriptional profiling of UTUC arising in the ureters and renal pelvis might be distinct. The observed difference might be related to immune response. Validation of these data in a larger independent cohort with analysis of the immune infiltrate is required. Citation Format: Gabriel Malouf, Roger Mouawad, Xiaoping Su, Hui Yao, Eva Comperat, Morgan Roupret, Jean-Philippe Spano, David Khayat. Transcriptionnal profiling of upper-tumor urothelial carcinomas. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 106.