title: 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.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Carreira
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Romanel
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Goodall
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Grist
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Roberta
authors.initials: R
authors.lastname: Ferraldeschi
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Susana
authors.initials: S
authors.lastname: Miranda
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Prandi
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: David
authors.initials: D
authors.lastname: Lorente
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Frenel
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Carmel
authors.initials: C
authors.lastname: Pezaro
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Aurelius
authors.initials: A
authors.lastname: Omlin
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Daniel Nava
authors.initials: DN
authors.lastname: Rodrigues
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK.
authors.forename: Penelope
authors.initials: P
authors.lastname: Flohr
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Nina
authors.initials: N
authors.lastname: Tunariu
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: S de Bono
authors.affiliation: Centre for Integrative Biology, University of Trento, Trento 38123, Italy. Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA. Institute for Precision Medicine, Weill Cornell Medical College, New York, NY 10021, USA. gerhardt.attard@icr.ac.uk demichelis@science.unitn.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Demichelis
authors.affiliation: The Institute of Cancer Research, London SM2 5NG, UK. Royal Marsden National Health Service Foundation Trust, London SM2 5PT, UK. gerhardt.attard@icr.ac.uk demichelis@science.unitn.it.
authors.forename: Gerhardt
authors.initials: G
authors.lastname: Attard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D002999:Clone Cells; D056915:DNA Copy Number Variations; D005938:Glucocorticoids / Q000008:administration & dosage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D011944:Receptors, Androgen / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics; D000071230:Transcriptional Regulator ERG
chemical_list: C072312:ERG protein, human; D005938:Glucocorticoids; D011944:Receptors, Androgen; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG