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 intra-patient 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 inter-individual and intra-individual heterogeneity.
Molecular cancer research : MCR. 2019 Mar 27 [Epub ahead of print]
Rahul R Aggarwal, David A Quigley, Jiaoti Huang, Li Zhang, Tomasz M Beer, Matthew B Rettig, Rob E Reiter, Martin E Gleave, George V Thomas, Adam Foye, Denise Playdle, Paul Lloyd, Kim N Chi, Christopher P Evans, Primo N Lara, Felix Y Feng, Joshi J Alumkal, Eric J Small
Hematology & Oncology, University of California, San Francisco ., Epidemiology and Biostatistics, University of California, San Francisco., Department of Pathology, Duke University School of Medicine., Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco., Hematology & Medical Oncology, OHSU Knight Cancer Institute., Department of Urology, School of Medicine, University of California Los Angeles., Dept of Urology, University of California Los Angeles., Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia., OHSU Knight Cancer Institute, OHSU Knight Cancer Institute., Medical Oncology, UCSF Helen Diller Family Comprehensive Cancer Center., Medicine Hematology/ Oncology, University of California, San Francisco., Hematology & Oncology, University of California, San Francisco., Vancouver Centre, British Columbia Cancer Agency., Department of Urologic Surgery, University of California, Davis., Internal Medicine, University of California Davis Comprehensive Cancer Center., Radiation Oncology, Helen Diller Comprehensive Cancer Center, University of California, San Francisco., Knight Cancer Institute, Department of Molecular and Medical Genetics, Oregon Health & Science University., Medical Oncology, University of California, San Francisco.