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,...

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Veröffentlicht in:Oncogene 2018-05, Vol.37 (22), p.3039-3044
Hauptverfasser: Shen, Peiye, Jing, Ying, Zhang, Ruiyun, Cai, Mei-Chun, Ma, Pengfei, Chen, Haige, Zhuang, Guanglei
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container_end_page 3044
container_issue 22
container_start_page 3039
container_title Oncogene
container_volume 37
creator Shen, Peiye
Jing, Ying
Zhang, Ruiyun
Cai, Mei-Chun
Ma, Pengfei
Chen, Haige
Zhuang, Guanglei
description 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.
doi_str_mv 10.1038/s41388-018-0192-5
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subjects 14/1
38
45
45/23
45/91
631/67/1059/2326
631/67/69
Age
APOBEC Deaminases - genetics
Apoptosis
Aristolochic acid
Bladder cancer
Brief Communication
Carcinoma, Neuroendocrine - genetics
Care and treatment
Cell Biology
Diagnosis
ErbB-2 protein
Etiology
Gene expression
Gene Expression Profiling
Gene Regulatory Networks
Genetic aspects
Genetic Association Studies
Genetic Predisposition to Disease
Genetic screening
Genomes
Genotype
Health aspects
High-Throughput Nucleotide Sequencing - methods
Human Genetics
Humans
Identification and classification
Internal Medicine
Malignancy
Medicine
Medicine & Public Health
Methods
Mutagenesis
Mutation
Neuroendocrine tumors
Oncology
p53 Protein
Receptor, ErbB-2 - genetics
Retinoblastoma Binding Proteins - genetics
Ribonucleic acid
RNA
Tumor cells
Tumor Suppressor Protein p53 - genetics
Ubiquitin-Protein Ligases - genetics
Urinary bladder
Urinary bladder carcinoma
Urinary Bladder Neoplasms - genetics
Urothelial cancer
Urothelial carcinoma
Whole Exome Sequencing - methods
Whole Genome Sequencing - methods
title Comprehensive genomic profiling of neuroendocrine bladder cancer pinpoints molecular origin and potential therapeutics
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