Tumor clone dynamics in lethal prostate cancer

被引：287

作者：

Carreira, Suzanne ^{[1
]}

Romanel, Alessandro ^{[2
]}

Goodall, Jane ^{[1
]}

Grist, Emily ^{[1
,3
]}

Ferraldeschi, Roberta ^{[1
,3
]}

Miranda, Susana ^{[1
]}

Prandi, Davide ^{[2
]}

Lorente, David ^{[1
,3
]}

Frenel, Jean-Sebastien ^{[1
]}

Pezaro, Carmel ^{[1
,3
]}

Omlin, Aurelius ^{[1
,3
]}

Rodrigues, Daniel Nava ^{[1
]}

Flohr, Penelope ^{[1
]}

Tunariu, Nina ^{[1
,3
]}

de Bono, Johann S. ^{[1
,3
]}

Demichelis, Francesca ^{[2
,4
,5
]}

Attard, Gerhardt ^{[1
,3
]}

机构：

[1] Inst Canc Res, London SM2 5NG, England

[2] Univ Trento, Ctr Integrat Biol, I-38123 Trento, Italy

[3] Royal Marsden Natl Hlth Serv Fdn Trust, London SM2 5PT, England

[4] Weill Cornell Med Coll, Inst Computat Biomed, New York, NY 10021 USA

[5] Weill Cornell Med Coll, Inst Precis Med, New York, NY 10021 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2014年 / 6卷 / 254期

关键词：

ANDROGEN-RECEPTOR GENE; ABIRATERONE ACETATE; ENZALUTAMIDE MDV3100; ANTITUMOR-ACTIVITY; ANTIANDROGEN; FUSION; ORIGIN; ERG; HETEROGENEITY; MUTATIONS;

D O I：

10.1126/scitranslmed.3009448

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

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