Molecular characterization of neuroendocrinelike bladder cancer

José Batista Da Costa, Ewan A. Gibb, Trinity J. Bivalacqua, Yang Liu, Htoo Zarni Oo, David T. Miyamoto, Mohammed Alshalalfa, Elai Davicioni, Jonathan Wright, Marc A. Dall'Era, James Douglas, Joost L. Boormans, Michiel S. Van Der Heijden, Chin Lee Wu, Bas W.G. Van Rhijn, Shilpa Gupta, Petros Grivas, Kent W. Mouw, Paari Murugan, Ladan FazliSeong Ra, Badrinath R. Konety, Roland Seiler, Siamak Daneshmand, Omar Y. Mian, Jason A. Efstathiou, Yair Lotan, Peter C. Black

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni-and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65%NE-like vs. 82%overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

Original languageEnglish (US)
Pages (from-to)3908-3920
Number of pages13
JournalClinical Cancer Research
Volume25
Issue number13
DOIs
StatePublished - Jan 1 2019

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Urinary Bladder Neoplasms
Neuroendocrine Tumors
Cluster Analysis
Factor IX
Muscles
Urinary Bladder
Neuroendocrine Carcinoma
Neoplasms
Cystectomy
Survival Analysis
Transcriptome
Disease-Free Survival
Histology
Research Design
Mortality
Genes
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Da Costa, J. B., Gibb, E. A., Bivalacqua, T. J., Liu, Y., Zarni Oo, H., Miyamoto, D. T., ... Black, P. C. (2019). Molecular characterization of neuroendocrinelike bladder cancer. Clinical Cancer Research, 25(13), 3908-3920. https://doi.org/10.1158/1078-0432.CCR-18-3558

Molecular characterization of neuroendocrinelike bladder cancer. / Da Costa, José Batista; Gibb, Ewan A.; Bivalacqua, Trinity J.; Liu, Yang; Zarni Oo, Htoo; Miyamoto, David T.; Alshalalfa, Mohammed; Davicioni, Elai; Wright, Jonathan; Dall'Era, Marc A.; Douglas, James; Boormans, Joost L.; Van Der Heijden, Michiel S.; Wu, Chin Lee; Van Rhijn, Bas W.G.; Gupta, Shilpa; Grivas, Petros; Mouw, Kent W.; Murugan, Paari; Fazli, Ladan; Ra, Seong; Konety, Badrinath R.; Seiler, Roland; Daneshmand, Siamak; Mian, Omar Y.; Efstathiou, Jason A.; Lotan, Yair; Black, Peter C.

In: Clinical Cancer Research, Vol. 25, No. 13, 01.01.2019, p. 3908-3920.

Research output: Contribution to journalArticle

Da Costa, JB, Gibb, EA, Bivalacqua, TJ, Liu, Y, Zarni Oo, H, Miyamoto, DT, Alshalalfa, M, Davicioni, E, Wright, J, Dall'Era, MA, Douglas, J, Boormans, JL, Van Der Heijden, MS, Wu, CL, Van Rhijn, BWG, Gupta, S, Grivas, P, Mouw, KW, Murugan, P, Fazli, L, Ra, S, Konety, BR, Seiler, R, Daneshmand, S, Mian, OY, Efstathiou, JA, Lotan, Y & Black, PC 2019, 'Molecular characterization of neuroendocrinelike bladder cancer', Clinical Cancer Research, vol. 25, no. 13, pp. 3908-3920. https://doi.org/10.1158/1078-0432.CCR-18-3558
Da Costa JB, Gibb EA, Bivalacqua TJ, Liu Y, Zarni Oo H, Miyamoto DT et al. Molecular characterization of neuroendocrinelike bladder cancer. Clinical Cancer Research. 2019 Jan 1;25(13):3908-3920. https://doi.org/10.1158/1078-0432.CCR-18-3558
Da Costa, José Batista ; Gibb, Ewan A. ; Bivalacqua, Trinity J. ; Liu, Yang ; Zarni Oo, Htoo ; Miyamoto, David T. ; Alshalalfa, Mohammed ; Davicioni, Elai ; Wright, Jonathan ; Dall'Era, Marc A. ; Douglas, James ; Boormans, Joost L. ; Van Der Heijden, Michiel S. ; Wu, Chin Lee ; Van Rhijn, Bas W.G. ; Gupta, Shilpa ; Grivas, Petros ; Mouw, Kent W. ; Murugan, Paari ; Fazli, Ladan ; Ra, Seong ; Konety, Badrinath R. ; Seiler, Roland ; Daneshmand, Siamak ; Mian, Omar Y. ; Efstathiou, Jason A. ; Lotan, Yair ; Black, Peter C. / Molecular characterization of neuroendocrinelike bladder cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 13. pp. 3908-3920.
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title = "Molecular characterization of neuroendocrinelike bladder cancer",
abstract = "Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5{\%} to 15{\%} of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni-and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6{\%}) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1{\%} to 6.6{\%} of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65{\%}NE-like vs. 82{\%}overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.",
author = "{Da Costa}, {Jos{\'e} Batista} and Gibb, {Ewan A.} and Bivalacqua, {Trinity J.} and Yang Liu and {Zarni Oo}, Htoo and Miyamoto, {David T.} and Mohammed Alshalalfa and Elai Davicioni and Jonathan Wright and Dall'Era, {Marc A.} and James Douglas and Boormans, {Joost L.} and {Van Der Heijden}, {Michiel S.} and Wu, {Chin Lee} and {Van Rhijn}, {Bas W.G.} and Shilpa Gupta and Petros Grivas and Mouw, {Kent W.} and Paari Murugan and Ladan Fazli and Seong Ra and Konety, {Badrinath R.} and Roland Seiler and Siamak Daneshmand and Mian, {Omar Y.} and Efstathiou, {Jason A.} and Yair Lotan and Black, {Peter C.}",
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T1 - Molecular characterization of neuroendocrinelike bladder cancer

AU - Da Costa, José Batista

AU - Gibb, Ewan A.

AU - Bivalacqua, Trinity J.

AU - Liu, Yang

AU - Zarni Oo, Htoo

AU - Miyamoto, David T.

AU - Alshalalfa, Mohammed

AU - Davicioni, Elai

AU - Wright, Jonathan

AU - Dall'Era, Marc A.

AU - Douglas, James

AU - Boormans, Joost L.

AU - Van Der Heijden, Michiel S.

AU - Wu, Chin Lee

AU - Van Rhijn, Bas W.G.

AU - Gupta, Shilpa

AU - Grivas, Petros

AU - Mouw, Kent W.

AU - Murugan, Paari

AU - Fazli, Ladan

AU - Ra, Seong

AU - Konety, Badrinath R.

AU - Seiler, Roland

AU - Daneshmand, Siamak

AU - Mian, Omar Y.

AU - Efstathiou, Jason A.

AU - Lotan, Yair

AU - Black, Peter C.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni-and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65%NE-like vs. 82%overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

AB - Purpose: Neuroendocrine (NE) bladder carcinoma is a rare and aggressive variant. Molecular subtyping studies have found that 5% to 15% of muscle-invasive bladder cancer (MIBC) have transcriptomic patterns consistent with NE bladder cancer in the absence of NE histology. The clinical implications of this NE-like subtype have not been explored in depth. Experimental Design: Transcriptome-wide expression profiles were generated for MIBC collected from 7 institutions and clinical-use of Decipher Bladder. Using unsupervised clustering, we generated a clustering solution on a prospective training cohort (PTC; n = 175), developed single-sample classifiers to predict NE tumors, and evaluated the resultant models on a testing radical cystectomy (RC) cohort (n = 225). A random forest model was finalized and applied to 5 validation cohorts (n = 1302). Uni-and multivariable survival analyses were used to characterize clinical outcomes. Results: In the training cohort (PTC), hierarchical clustering using an 84-gene panel showed a cluster of 8 patients (4.6%) with highly heterogeneous expression of NE markers in the absence of basal or luminal marker expression. NE-like tumors were identified in 1% to 6.6% of cases in validation cohorts. Patients with NE-like tumors had significantly worse 1-year progression-free survival (65%NE-like vs. 82%overall; P = 0.046) and, after adjusting for clinical and pathologic factors, had a 6.4-fold increased risk of all-cause mortality (P = 0.001). IHC confirmed the neuronal character of these tumors. Conclusions: A single-patient classifier was developed that identifies patients with histologic urothelial cancer harboring a NE transcriptomic profile. These tumors represent a high-risk subgroup of MIBC, which may require different treatment.

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