Comprehensive genomic profiling of neuroendocrine bladder cancer pinpoints molecular origin and potential therapeutics.

Neuroendocrine bladder cancer is a relatively rare but often lethal malignancy, with cell of origin, oncogenomic architecture and standard treatment poorly defined. Here we performed comprehensive whole-genome and transcriptome sequencing on a unique cohort of genitourinary neuroendocrine neoplasms, mainly small cell carcinomas of the urinary bladder. The mutational landscape and signatures of neuroendocrine bladder cancer strikingly resembled those in conventional urothelial carcinoma, along with typically mixed histologies, supporting a common cellular origin. We identified pervasive age-related and APOBEC-mediated mutagenesis patterns, and one patient displayed a somatic fingerprint attributable to aristolochic acid exposure, an established etiology of urothelial cell carcinoma. Deep RNA sequencing revealed dysregulated tumorigenic pathways and novel fusion transcripts, including a targetable in-frame PVT1-ERBB2 variant associated with aberrant expression of ERBB2 gene (encoding HER2 receptor). Furthermore, we provided preliminary evidence that combined TP53 and RB1 depletion favored lineage switching from oncogene-addicted urothelial cancer cells to neuroendocrine-like tumor cells, and resulted in decreased response to targeted agents. Together, these data present the first high-resolution genomic portrait of neuroendocrine bladder cancer, which holds important implications for the biological understanding and rational treatment of this deadly disease.