Divergent clonal evolution of castration resistant neuroendocrine prostate cancer

By H. Beltran, D. Prandi, J. Mosquera, M. Benelli, L. Puca, J. Cyrta, C. Marotz, Eugenia G. Giannopoulou, B. V. Chakravarthi, S. Varambally and 9 more. Nature Medicine, 2016

1,503 citations recorded by the source corpus.

An increasingly recognized resistance mechanism to androgen receptor (AR)-directed therapy in prostate cancer involves epithelial plasticity, in which tumor cells demonstrate low to absent AR expression and often have neuroendocrine features. The etiology and molecular basis for this 'alternative' treatment-resistant cell state remain incompletely understood. Here, by analyzing whole-exome sequencing data of metastatic biopsies from patients, we observed substantial genomic overlap between castration-resistant tumors that were histologically characterized as prostate adenocarcinomas (CRPC-Adeno) and neuroendocrine prostate cancer (CRPC-NE); analysis of biopsy samples from the same individuals over time points to a model most consistent with divergent clonal evolution. Genome-wide DNA methylation analysis revealed marked epigenetic differences between CRPC-NE tumors and CRPC-Adeno, and also designated samples of CRPC-Adeno with clinical features of AR independence as CRPC-NE, suggesting that epigenetic modifiers may play a role in the induction and/or maintenance of this treatment-resistant state. This study supports the emergence of an alternative, 'AR-indifferent' cell state through divergent clonal evolution as a mechanism of treatment resistance in advanced prostate cancer.

Subfields: Oncology, Pulmonary and Respiratory Medicine, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/2e2d1dbd94ce746afc91b11c927d6540757c6d4d

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Oncology

1. Nikolaus Schultz
2. C. Sawyers
3. R. DePinho
4. E. Scholar
5. A. Arora

In Pulmonary and Respiratory Medicine

1. Arul M. Chinnaiyan
2. C. Sawyers
3. Mark A. Rubin
4. R. Vessella
5. M. Hallek

Citations in the corpus

• Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling (2017, methodology): “Gene expression programs of the tumors classified by immunohistochemistry (IHC) supported these distinct subtypes using 10-gene signatures that were concordant with previously published gene sets indicative of NE and AR pathway activity (Figures 1C, S1A, and S1B) (Beltran et al., 2016; Hieronymus et”
• Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. (2018, neutral): “741 White 163 (81) 23 (84) 108 (81) 32 (76) African American 12 (6) 1 (4) 9 (7) 2 (5) Asian 5 (2) 0 4 (3) 1 (2) Native American 1 (, 1) 0 1 (1) 0 Not reported 21 (10) 3 (12) 11 (8) 7 (17) Gleason score at diagnosis .”
• The long tail of oncogenic drivers in prostate cancer (2018, neutral): “All clinicopathological annotations were obtained from the original papers 1,2,4,7–9 .”
• Genomic correlates of clinical outcome in advanced prostate cancer (2019, methodology): “Some 262 216 179 217 81 47 81 223 99 185 8 8 63 98 17 173 43 12 89 9 35 173 20 7 7 36 exon6-3'UTR exon5-8 exon4-9 exon2-5 exon2-4 exon2-CE4' exon1-4 exon1-3 exon1-CE4 exon3-5 exon2-3(long exon3) ARv8es=AR-V14 (7-9) ARv78es=AR-V13 (6-9) ARv7es (6-8) ARv567es (4-8) ARv5es (4-6) AR-V9 (3-CE5) AR-V8 (3-”
• Genetics and biology of prostate cancer (2018, background): “…tumors and mCRPC have identified recurrentDNAcopy number changes,mutations, rearrangements, and gene fusions (Table 1; Taylor et al. 2010; Barbieri et al. 2012; Grasso et al. 2012; Weischenfeldt et al. 2013; The Cancer Genome Atlas Research Network 2015; Beltran et al. 2016b; Fraser et al. 2017).”