Selection of metastasis competent subclones in the tumour interior.
Selection of metastasis competent subclones in the tumour interior.
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DOI：
10.1038/s41559-021-01456-6
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发表时间：
2021-07
影响因子：
16.8
通讯作者：
Litchfield K
中科院分区：
文献类型：
--
作者：
Zhao Y;Fu X;Lopez JI;Rowan A;Au L;Fendler A;Hazell S;Xu H;Horswell S;Shepherd STC;Spain L;Byrne F;Stamp G;O'Brien T;Nicol D;Augustine M;Chandra A;Rudman S;Toncheva A;Pickering L;Sahai E;Larkin J;Bates PA;Swanton C;Turajlic S;TRACERx Renal Consortium;Litchfield K
人们越来越多地描述实体瘤生长的遗传进化特征，但亚克隆生长的空间和物理性质仍不清楚。在这里，我们利用来自透明细胞肾细胞癌患者的 102 个宏观全肿瘤图像，以及来自 756 个活检的匹配遗传和表型数据。利用数字图像处理流程，肾脏病理学家标记了肿瘤和正常组织之间的边界，并将边界线和活检区域的位置提取到 X 和 Y 坐标。然后，我们将坐标与基因组数据集成，以绘制精确的空间亚克隆位置图，揭示遗传上不同的亚克隆如何在空间上生长和进化。我们在肿瘤中心观察到一种晚期且更具侵袭性的亚克隆生长表型，其特征是体细胞拷贝数改变负担增加、坏死、增殖率和 Fuhrman 等级更高。此外，我们发现转移亚克隆优先起源于肿瘤中心。总的来说，这些观察结果表明肿瘤内部存在加速进化的模型，恶劣的缺氧环境条件导致驱动 SCNA 由于选择性优势而有更大的机会出现和扩展。肿瘤亚克隆的生长本质上主要是空间连续的。我们仅发现两例亚克隆扩散，均与转移相关。空间上最大的亚克隆由驱动体细胞拷贝数改变主导，这表明在获得这些改变后可以赋予亚克隆很大的选择优势。总之，空间动力学与基因组改变密切相关，并在肿瘤进化中发挥重要作用。
The genetic evolutionary features of solid tumour growth are becoming increasingly described but the spatial and physical nature of subclonal growth remains unclear. Here, we utilise 102 macroscopic whole tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilising a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X- and Y-coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterised by an elevated burden of somatic copy number alterations, higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasising subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading greater opportunity for driver SCNAs to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, both associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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影响因子：
11.2
作者：
Endesfelder D;Burrell R;Kanu N;McGranahan N;Howell M;Parker PJ;Downward J;Swanton C;Kschischo M
通讯作者：
Kschischo M
影响因子：
16
作者：
Coquelle, A;Toledo, F;Debatisse, M
通讯作者：
Debatisse, M
影响因子：
30.8
作者：
Bhandari, Vinayak;Hoey, Christianne;Bristow, Robert G.
通讯作者：
Bristow, Robert G.
DOI：
10.2217/fon.13.66
发表时间：
2013-08
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Foty RA
通讯作者：
Foty RA
影响因子：
64.8
作者：
通讯作者：
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