Abstract LB-320: Obligate lesions and diverse evolutionary patterns drive small cell bladder cancer

Abstract

Abstract Small cell bladder cancer (SCBC) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCBC is histologically indistinguishable from small cell lung cancer, a shared pathogenesis and cell of origin has been proposed. To determine whether SCBCs arise from a pre-existent urothelial carcinoma or share a molecular pathogenesis in common with small cell lung cancer, we performed integrative analysis of 61 SCBC patients to identify histology- and organ-specific similarities and differences with urothelial carcinomas and small cell lung cancers. SCBC has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. Obligate mutations in TP53, RB1, or the TERT promoter were present in nearly all samples. While these events arose early in all affected tumors, reflecting an evolutionary branch point that drove small cell lineage differentiation, they were not the founding transforming event, as they were often preceded by diverse and less common driver mutations many of which are common in bladder urothelial cancers but not small cell lung tumors. The majority of patient tumors (72%) also underwent whole-genome duplication (WGD). While arising at different chronological points in the evolution of the disease, WGD was often preceded by biallelic mutations in TP53 with retention of two intact copies. Together, our findings indicate that small cell cancers of the bladder and lung have a convergent but distinct pathogenesis and SCBCs likely arise from a cell of original shared with urothelial bladder cancer. Citation Format: Alexander Penson, Matthew T. Chang, Neil Desai, Nicholas D. Socci, Ronglai Shen, Venkatraman E. Seshan, Ritika Kundra, Adam Abeshouse, Agnes Viale, Eugene K. Cha, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Nikolaus Schultz, Michael F. Berger, Gopa Iyer, David B. Solit, Hikmat Al-Ahmadie, Barry S. Taylor. Obligate lesions and diverse evolutionary patterns drive small cell bladder cancer. [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 LB-320.