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Selection of metastasis competent subclones in the tumour interior.

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Date
2021-05-17
ICR Author
Au, Lewis
Shepherd, Scott
Stamp, Gordon
Larkin, James
Turajlic, Samra
Author
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
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Type
Journal Article
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Abstract
The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing 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, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing 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 to a greater opportunity for driver somatic copy number alterations 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, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that 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.
URI
https://repository.icr.ac.uk/handle/internal/5276
DOI
https://doi.org/10.1038/s41559-021-01456-6
https://doi.org/10.1038/s41559-021-01456-6
 
Collections
  • Clinical Studies
Subject
DNA Copy Number Variations
Evolution, Molecular
Genomics
Humans
Mutation
Neoplasms
Research team
Melanoma & Kidney Cancer
Experimental Pathology
Language
eng
Date accepted
2021-03-03
License start date
2021-05-17
Citation
Nature Ecology and Evolution, 2021, 5 (7), pp. 1033 - 1045
Publisher
NATURE RESEARCH

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