Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity

Rahul R. Aggarwal, David A. Quigley, Jiaoti Huang, Li Zhang, Tomasz (Tom) Beer, Matthew B. Rettig, Rob E. Reiter, Martin E. Gleave, George Thomas, Adam Foye, Denise Playdle, Paul Lloyd, Kim N. Chi, Christopher P. Evans, Primo N. Lara, Felix Y. Feng, Joshi Alumkal, Eric J. Small

Research output: Contribution to journalArticle

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Abstract

Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.

Original languageEnglish (US)
Pages (from-to)1235-1240
Number of pages6
JournalMolecular cancer research : MCR
Volume17
Issue number6
DOIs
StatePublished - Jun 1 2019

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Neuroendocrine Carcinoma
Neuroendocrine Cells
Small Cell Carcinoma
Prostatic Neoplasms
Genome
Adenocarcinoma
Castration
Phenotype
Biopsy
Neoplasms
Gene Expression Profiling

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity. / Aggarwal, Rahul R.; Quigley, David A.; Huang, Jiaoti; Zhang, Li; Beer, Tomasz (Tom); Rettig, Matthew B.; Reiter, Rob E.; Gleave, Martin E.; Thomas, George; Foye, Adam; Playdle, Denise; Lloyd, Paul; Chi, Kim N.; Evans, Christopher P.; Lara, Primo N.; Feng, Felix Y.; Alumkal, Joshi; Small, Eric J.

In: Molecular cancer research : MCR, Vol. 17, No. 6, 01.06.2019, p. 1235-1240.

Research output: Contribution to journalArticle

Aggarwal, RR, Quigley, DA, Huang, J, Zhang, L, Beer, TT, Rettig, MB, Reiter, RE, Gleave, ME, Thomas, G, Foye, A, Playdle, D, Lloyd, P, Chi, KN, Evans, CP, Lara, PN, Feng, FY, Alumkal, J & Small, EJ 2019, 'Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity', Molecular cancer research : MCR, vol. 17, no. 6, pp. 1235-1240. https://doi.org/10.1158/1541-7786.MCR-18-1101
Aggarwal, Rahul R. ; Quigley, David A. ; Huang, Jiaoti ; Zhang, Li ; Beer, Tomasz (Tom) ; Rettig, Matthew B. ; Reiter, Rob E. ; Gleave, Martin E. ; Thomas, George ; Foye, Adam ; Playdle, Denise ; Lloyd, Paul ; Chi, Kim N. ; Evans, Christopher P. ; Lara, Primo N. ; Feng, Felix Y. ; Alumkal, Joshi ; Small, Eric J. / Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity. In: Molecular cancer research : MCR. 2019 ; Vol. 17, No. 6. pp. 1235-1240.
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abstract = "Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.",
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AU - Quigley, David A.

AU - Huang, Jiaoti

AU - Zhang, Li

AU - Beer, Tomasz (Tom)

AU - Rettig, Matthew B.

AU - Reiter, Rob E.

AU - Gleave, Martin E.

AU - Thomas, George

AU - Foye, Adam

AU - Playdle, Denise

AU - Lloyd, Paul

AU - Chi, Kim N.

AU - Evans, Christopher P.

AU - Lara, Primo N.

AU - Feng, Felix Y.

AU - Alumkal, Joshi

AU - Small, Eric J.

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