Tumor clone dynamics in lethal prostate cancer.
Tumor clone dynamics in lethal prostate cancer.
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DOI：
10.1126/scitranslmed.3009448
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发表时间：
2014-09-17
影响因子：
17.1
通讯作者：
Attard G
中科院分区：
文献类型：
--
作者：
Carreira S;Romanel A;Goodall J;Grist E;Ferraldeschi R;Miranda S;Prandi D;Lorente D;Frenel JS;Pezaro C;Omlin A;Rodrigues DN;Flohr P;Tunariu N;S de Bono J;Demichelis F;Attard G
目前尚不清楚在致命性前列腺癌的整个过程中，是否有单个克隆人转移并保持主导地位。我们通过对16例ERG阳性患者的连续血浆和肿瘤样本进行测序，描述了疾病进展不同阶段的克隆结构异质性。通过鉴定常见的21q22、8p21和10q23缺失的克隆性，我们在转移性疾病中鉴定了在组织和循环中不同表现的多个独立克隆。为了举例说明我们研究的临床实用价值，我们随后显示了临床进展与糖皮质激素激活的雄激素受体(AR)突变的出现之间的时间相关性，在服用阿比特龙、强的松龙或地塞米松的患者中，约有20%的患者进展。抗性无性系表现出时间和空间异质性的复杂动态，表明抗性在不同地点的不同机制取决于处理选择压力的出现和消退。这引入了一种管理模式，要求对晚期前列腺癌患者进行血浆和肿瘤活检的顺序监测，以确保当他们成为潜在的疾病驱动因素时，及早停止使用药物。
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.
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影响因子：
11.2
作者：
Attard, Gerhardt;Swermenhuis, Joost F.;de Bono, Johann S.
通讯作者：
de Bono, Johann S.
影响因子：
11.2
作者：
Richards J;Lim AC;Hay CW;Taylor AE;Wingate A;Nowakowska K;Pezaro C;Carreira S;Goodall J;Arlt W;McEwan IJ;de Bono JS;Attard G
通讯作者：
Attard G
影响因子：
7.7
作者：
Balbas MD;Evans MJ;Hosfield DJ;Wongvipat J;Arora VK;Watson PA;Chen Y;Greene GL;Shen Y;Sawyers CL
通讯作者：
Sawyers CL
影响因子：
12.3
作者：
Prandi D;Baca SC;Romanel A;Barbieri CE;Mosquera JM;Fontugne J;Beltran H;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F
DOI：
10.1073/pnas.0507904102
发表时间：
2005-11-08
影响因子：
11.1
作者：
Diehl, F;Li, M;Vogelstein, B
通讯作者：
Vogelstein, B