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

Matthew T. Chang, Alexander Penson, Neil B. Desai, Nicholas D. Socci, Ronglai Shen, Venkatraman E. Seshan, Ritika Kundra, Adam Abeshouse, Agnes Viale, Eugene K. Cha, Xueli Hao, Victor E. Reuter, Charles M. Rudin, Bernard H. Bochner, Jonathan E. Rosenberg, Dean F. Bajorin, Nikolaus Schultz, Michael F. Berger, Gopa Iyer, David B. Solit & 2 others Hikmat A. Al-Ahmadie, Barry S. Taylor

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1965-1973
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number8
DOIs
StatePublished - Apr 15 2018

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Small Cell Carcinoma
Small Cell Lung Carcinoma
Urinary Bladder Neoplasms
Urinary Bladder
Mutation
Genome
Neoplasms
Neuroendocrine Tumors
Cell Lineage
Cell Differentiation
Histology
Research Design
Carcinoma
Lung
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis. / Chang, Matthew T.; Penson, Alexander; Desai, Neil B.; Socci, Nicholas D.; Shen, Ronglai; Seshan, Venkatraman E.; Kundra, Ritika; Abeshouse, Adam; Viale, Agnes; Cha, Eugene K.; Hao, Xueli; Reuter, Victor E.; Rudin, Charles M.; Bochner, Bernard H.; Rosenberg, Jonathan E.; Bajorin, Dean F.; Schultz, Nikolaus; Berger, Michael F.; Iyer, Gopa; Solit, David B.; Al-Ahmadie, Hikmat A.; Taylor, Barry S.

In: Clinical Cancer Research, Vol. 24, No. 8, 15.04.2018, p. 1965-1973.

Research output: Contribution to journalArticle

Chang, MT, Penson, A, Desai, NB, Socci, ND, Shen, R, Seshan, VE, Kundra, R, Abeshouse, A, Viale, A, Cha, EK, Hao, X, Reuter, VE, Rudin, CM, Bochner, BH, Rosenberg, JE, Bajorin, DF, Schultz, N, Berger, MF, Iyer, G, Solit, DB, Al-Ahmadie, HA & Taylor, BS 2018, 'Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis', Clinical Cancer Research, vol. 24, no. 8, pp. 1965-1973. https://doi.org/10.1158/1078-0432.CCR-17-2655
Chang, Matthew T. ; Penson, Alexander ; Desai, Neil B. ; Socci, Nicholas D. ; Shen, Ronglai ; Seshan, Venkatraman E. ; Kundra, Ritika ; Abeshouse, Adam ; Viale, Agnes ; Cha, Eugene K. ; Hao, Xueli ; Reuter, Victor E. ; Rudin, Charles M. ; Bochner, Bernard H. ; Rosenberg, Jonathan E. ; Bajorin, Dean F. ; Schultz, Nikolaus ; Berger, Michael F. ; Iyer, Gopa ; Solit, David B. ; Al-Ahmadie, Hikmat A. ; Taylor, Barry S. / Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 8. pp. 1965-1973.
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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.",
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T1 - Small-cell carcinomas of the bladder and lung are characterized by a convergent but distinct pathogenesis

AU - Chang, Matthew T.

AU - Penson, Alexander

AU - Desai, Neil B.

AU - Socci, Nicholas D.

AU - Shen, Ronglai

AU - Seshan, Venkatraman E.

AU - Kundra, Ritika

AU - Abeshouse, Adam

AU - Viale, Agnes

AU - Cha, Eugene K.

AU - Hao, Xueli

AU - Reuter, Victor E.

AU - Rudin, Charles M.

AU - Bochner, Bernard H.

AU - Rosenberg, Jonathan E.

AU - Bajorin, Dean F.

AU - Schultz, Nikolaus

AU - Berger, Michael F.

AU - Iyer, Gopa

AU - Solit, David B.

AU - Al-Ahmadie, Hikmat A.

AU - Taylor, Barry S.

PY - 2018/4/15

Y1 - 2018/4/15

N2 - 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.

AB - 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.

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