Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.
Copy number architectures define treatment-mediated selection of lethal prostate cancer clones.
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DOI：
10.1038/s41467-023-40315-9
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发表时间：
2023-08-10
影响因子：
16.6
通讯作者：
Attard, Gerhardt
中科院分区：
文献类型：
--
作者：
Hasan, A. M. Mahedi;Cremaschi, Paolo;Wetterskog, Daniel;Jayaram, Anuradha;Wong, Stephen Q.;Williams, Scott;Pasam, Anupama;Trigos, Anna;Trujillo, Blanca;Grist, Emily;Friedrich, Stefanie;Vainauskas, Osvaldas;Parry, Marina;Ismail, Mazlina;Devlies, Wout;Wingate, Anna;Linch, Mark;Naceur-Lombardelli, Cristina;Swanton, Charles;Jamal-Hanjani, Mariam;Lise, Stefano;Sandhu, Shahneen;Attard, Gerhardt
尽管最初对激素治疗有反应，但转移性前列腺癌总是演变到致命状态。为了描述逃避治疗的转移瘤在患者内部的进化关系，我们对10名死于前列腺癌的男性死后采集的11个器官的167个转移区域进行全基因组拷贝数分析和针对雄激素受体(AR)的定制方法。我们从每个患者的转移瘤中识别聚集在AR周围的多样化和患者特有的改变，证据表明个体内独立获得了相关的基因组变化，在一些患者中，存在AR中性克隆的共存。使用泛常染色体拷贝数变化的基因组边界，我们确认了一个跨越转移和诊断活检的共同起源克隆，并在个别患者中确定了转移的显性克隆占据的簇，具有不同的常染色体拷贝数改变。这些常染色体定义的簇具有簇特异性AR基因结构的特征，在两个指数病例中，其拓扑结构比偶然情况下更一致(p值分别为3.07 × 10−8和6.4 × 10−4)。与解剖部位的结合表明了扩散的模式和基因组分歧点。在这里，我们表明，拷贝数边界识别治疗选择的克隆具有假定不同的致死轨迹。前列腺癌转移中雄激素受体(AR)基因改变的异质性仍未解决。在这里，作者描述了来自10名前列腺癌患者的空间分离的致命转移的AR基因组的复杂性，并研究了AR的变化是如何演变的。
Despite initial responses to hormone treatment, metastatic prostate cancer invariably evolves to a lethal state. To characterize the intra-patient evolutionary relationships of metastases that evade treatment, we perform genome-wide copy number profiling and bespoke approaches targeting the androgen receptor (AR) on 167 metastatic regions from 11 organs harvested post-mortem from 10 men who died from prostate cancer. We identify diverse and patient-unique alterations clustering around the AR in metastases from every patient with evidence of independent acquisition of related genomic changes within an individual and, in some patients, the co-existence of AR-neutral clones. Using the genomic boundaries of pan-autosome copy number changes, we confirm a common clone of origin across metastases and diagnostic biopsies, and identified in individual patients, clusters of metastases occupied by dominant clones with diverged autosomal copy number alterations. These autosome-defined clusters are characterized by cluster-specific AR gene architectures, and in two index cases are topologically more congruent than by chance (p-values 3.07 × 10−8 and 6.4 × 10−4). Integration with anatomical sites suggests patterns of spread and points of genomic divergence. Here, we show that copy number boundaries identify treatment-selected clones with putatively distinct lethal trajectories. The heterogeneity of androgen receptor (AR) gene alterations across metastases in prostate cancer remains unresolved. Here, the authors characterise AR genomic complexity across spatially separated lethal metastases from 10 prostate cancer patients and investigate how AR alterations evolve.
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DOI：
10.1093/annonc/mdu479
发表时间：
2015-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Favero F;Joshi T;Marquard AM;Birkbak NJ;Krzystanek M;Li Q;Szallasi Z;Eklund AC
通讯作者：
Eklund AC
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
5.4
作者：
Dentro, Stefan C.;Wedge, David C.;Van Loo, Peter
通讯作者：
Van Loo, Peter
影响因子：
5.8
作者：
de Vienne, Damien M.;Giraud, Tatiana;Martin, Olivier C.
通讯作者：
Martin, Olivier C.
DOI：
10.1073/pnas.1411446111
发表时间：
2014-07-29
影响因子：
11.1
作者：
Hieronymus, Haley;Schultz, Nikolaus;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.