Abstract LB-174: Examining the genomic differences between upper and lower tract urothelial carcinomas

Abstract

Abstract Background Urothelial carcinomas are capable of arising at multiple sites within the urinary tract. About 90% of cases originate in the urinary bladder (lower tract) and about 10% of cases emerge in the pelvis or ureter (upper tract). While these sites have similar histologic appearances, there are differences in their epidemiologic, clinical and pathologic characteristics, suggesting they may represent two distinct diseases. Previous studies have observed a more aggressive disease from patients with upper tract urothelial carcinoma (UTUC) versus patients with urothelial carcinoma of the bladder (UCB). Our aim was to examine whether the clinicopathological differences between upper and lower tract urothelial tumors are the result of differences in their scope of somatic genetic alterations. Methods Tumors and matched germline DNA from 59 patients with high-grade UTUC and 102 patients with high-grade UCB were extracted. The genomic profiles of these patients were analyzed and compared using a custom hybridization capture-based sequencing assay to identify point mutations, small insertions, deletions and copy number alterations of 230 cancer-associated genes. Results Average next-generation sequencing coverage for high-grade UTUC (674x) and UCB (762x) tumors. The comparison between the high-grade UTUC and UCB tumors identified significant differences in the prevalence of somatic alterations between these cohorts. Alterations in oncogene HRAS (13.6% UTUC vs. 1.0% UCB, p = 0.001) were more common in high-grade UTUC. Another oncogene FGFR3 (35.6% UTUC vs. 21.6% UCB, p = 0.065) was not significantly different between the UTUC and UCB cohorts. Genes identified as significantly less frequently altered in UTUC compared to UCB tumors included tumor suppressor genes TP53 (25.4% vs. 57.8%, p<0.001), RB1 (0.0% vs. 18.6%, p<0.001), and ARID1A (13.6% vs. 27.5%, p = 0.05). Conclusions While the genes with somatic alterations in upper and lower tract urothelial tumors were similar, we did identify significant differences in the prevalence of several recurrently altered genes including TP53, RB1, HRAS and ARID1A between UTUC and UCB cohorts. These findings may account for the divergence in clinical outcomes observed between these two disease sites and the high prevalence of actionable genomic targets may assist in the development of novel therapeutic approaches for these diseases. Citation Format: Sasinya N. Scott, John P. Sfakianos, Eugene K. Cha, Gopa Iyer, Emily C. Zabor, Philip H. Kim, A. A. Hakimi, Irina Ostrovnaya, Ricardo Ramirez, Aphrothiti J. Hanrahan, Neil Desai, Qinghu Ren, Arony Sun, Jonathan E. Rosenberg, Guido Dalbagni, Dean F. Bajorin, Michael F. Berger, Bernard H. Bochner, Hikmat Al-Ahmadie, David B. Solit, Jonathan A. Coleman. Examining the genomic differences between upper and lower tract urothelial carcinomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-174. doi:10.1158/1538-7445.AM2015-LB-174