Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis Journal Article

Authors: Chang, M. T.; Penson, A.; Desai, N. B.; Socci, N. D.; Shen, R.; Seshan, V. E.; Kundra, R.; Abeshouse, A.; Viale, A.; Cha, E. K.; Hao, X.; Reuter, V. E.; Rudin, C. M.; Bochner, B. H.; Rosenberg, J. E.; Bajorin, D. F.; Schultz, N.; Berger, M. F.; Iyer, G.; Solit, D. B.; Al-Ahmadie, H. A.; Taylor, B. S.
Article Title: Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis
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. © 2017 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 24
Issue: 8
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2018-04-01
Start Page: 1965
End Page: 1973
Language: English
DOI: 10.1158/1078-0432.ccr-17-2655
PROVIDER: scopus
PUBMED: 29180607
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Venkatraman Ennapadam Seshan
    283 Seshan
  2. Dean Bajorin
    383 Bajorin
  3. David Solit
    420 Solit
  4. Ronglai Shen
    126 Shen
  5. Gopakumar Vasudeva Iyer
    121 Iyer
  6. Neil B Desai
    35 Desai
  7. Bernard Bochner
    315 Bochner
  8. Agnes Viale
    203 Viale
  9. Nicholas D Socci
    182 Socci
  10. Michael Forman Berger
    373 Berger
  11. Victor Reuter
    890 Reuter
  12. Barry Stephen Taylor
    135 Taylor
  13. Nikolaus D Schultz
    193 Schultz
  14. Jonathan Eric Rosenberg
    210 Rosenberg
  15. Charles Rudin
    155 Rudin
  16. Eugene K. Cha
    56 Cha
  17. Matthew   Chang
    21 Chang
  18. Xueli   Hao
    10 Hao
  19. Alexander Vincent Penson
    14 Penson
  20. Ritika   Kundra
    15 Kundra