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

Oncogene volume 37, pages 3039–3044 (2018)Cite this article

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Abstract

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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81672514 to HC; 81472537 and 81672714 to GZ; 81502597 to YJ), Shanghai Natural Science Foundation (16ZR1420300 to HC), Foundation of Shanghai Hospital Development Center (SHDC12015125 to HC), the Grants from the State Key Laboratory of Oncogenes and Related Genes (no. 91-15-12 to GZ; SB17-06 to M-CC), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support (20161313 to GZ), the Shanghai Institutions of Higher Learning (Eastern Scholar to GZ), Shanghai Rising-Star Program (16QA1403600 to GZ), Shanghai Municipal Commission of Health and Family Planning (20174Y0189 to YJ and 20174Y0043 to M-CC).

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    Authors and Affiliations

    1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

      Peiye Shen, Ying Jing, Mei-Chun Cai, Pengfei Ma & Guanglei Zhuang

    2. School of Biomedical Engineering & Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China

      Peiye Shen

    3. Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

      Ruiyun Zhang & Haige Chen

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    1. Peiye Shen
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    Correspondence to Haige Chen or Guanglei Zhuang.

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    These authors contributed equally: Peiye Shen, Ying Jing, Ruiyun Zhang.

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    Shen, P., Jing, Y., Zhang, R. et al. Comprehensive genomic profiling of neuroendocrine bladder cancer pinpoints molecular origin and potential therapeutics. Oncogene 37, 3039–3044 (2018). https://doi.org/10.1038/s41388-018-0192-5

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