Tumor clone dynamics in lethal prostate cancer.

Abstract

It is unclear whether a single clone metastasizes and remains dominant over the course of lethal prostate cancer. We describe the clonal architectural heterogeneity at different stages of disease progression by sequencing serial plasma and tumor samples from 16 ERG-positive patients. By characterizing the clonality of commonly occurring deletions at 21q22, 8p21, and 10q23, we identified multiple independent clones in metastatic disease that are differentially represented in tissue and circulation. To exemplify the clinical utility of our studies, we then showed a temporal association between clinical progression and emergence of androgen receptor (AR) mutations activated by glucocorticoids in about 20% of patients progressing on abiraterone and prednisolone or dexamethasone. Resistant clones showed a complex dynamic with temporal and spatial heterogeneity, suggesting distinct mechanisms of resistance at different sites that emerged and regressed depending on treatment selection pressure. This introduces a management paradigm requiring sequential monitoring of advanced prostate cancer patients with plasma and tumor biopsies to ensure early discontinuation of agents when they become potential disease drivers.

• Authors: Suzanne Carreira, Alessandro Romanel, Jane Goodall, Emily Grist, Roberta Ferraldeschi, Susana Miranda, Davide Prandi, David Lorente, Jean-Sebastien Frenel, Carmel Pezaro, Aurelius Omlin, Daniel Nava Rodrigues, Penelope Flohr, Nina Tunariu, Johann S de Bono, Francesca Demichelis, Gerhardt Attard
• Journal: Science translational medicine (Sci Transl Med) Vol. 6 Issue 254 Pg. 254ra125 (Sep 17 2014) ISSN: 1946-6242 [Electronic] United States
• PMID: 25232177 (Publication Type: Journal Article)
• Copyright: Copyright © 2014, American Association for the Advancement of Science.

Chemical References

• ERG protein, human
• Glucocorticoids
• Receptors, Androgen
• Trans-Activators
• Transcriptional Regulator ERG

Topics

• Adult
• Aged
• Aged, 80 and over
• Chromosome Deletion
• Clone Cells
• DNA Copy Number Variations
• Glucocorticoids (administration & dosage)
• Humans
• Male
• Middle Aged
• Mutation
• Prostatic Neoplasms (genetics, pathology)
• Receptors, Androgen (genetics)
• Trans-Activators (genetics)
• Transcriptional Regulator ERG