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Clin Cancer Res. 2018 Apr 15;24(8):1965-1973. doi: 10.1158/1078-0432.CCR-17-2655. Epub 2017 Nov 27.

Small-Cell Carcinomas of the Bladder and Lung Are Characterized by a Convergent but Distinct Pathogenesis.

Author information

1
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.
2
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, California.
4
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Bioinformatics Core, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
9
Department of Medicine, Weill Cornell Medical College, Cornell University, New York, New York.
10
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York. taylorb@mskcc.org alahmadh@mskcc.org.
11
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. taylorb@mskcc.org alahmadh@mskcc.org.
#
Contributed equally

Abstract

Purpose: Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.Experimental Design: We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.Results: SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process. TP53, RB1, and TERT promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely 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. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in TP53 with retention of two intact copies.Conclusions: Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer. Clin Cancer Res; 24(8); 1965-73. ©2017 AACRSee related commentary by Oser and Jänne, p. 1775.

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