1. Selection of metastasis competent subclones in the tumour interior: TRACERx renal
- Author
-
Marcellus Augustine, David Nicol, Antonia Toncheva, Scott Shephard, Timothy O'Brien, Sarah Rudman, Stuart Horswell, Lisa Pickering, Fiona Byrne, Steve Hazell, Andrew D. Rowan, Samra Turajlic, Annika Fendler, José I. López, Paul A. Bates, Xiao Fu, Hang Xu, Yue Zhao, Ashish Chandra, Lewis Au, Gordon Stamp, Kevin Litchfield, James E. Larkin, Erik Sahai, Lavinia Spain, and Charles Swanton
- Subjects
medicine ,Cancer research ,Biology ,medicine.disease ,Selection (genetic algorithm) ,Metastasis - Abstract
While the genetic evolutionary features of solid tumour growth are becoming increasingly described, the spatial and physical nature of subclonal growth remains unclear. Here we utilise 102 macroscopic whole tumour images from clear cell renal cell carcinoma (ccRCC) patients, with matched genetic and phenotypic data from 756 biopsies. Utilising a digital image processing pipeline the boundaries between tumour and normal tissue were marked by a renal pathologist, and positions of boundary line and biopsy regions were extracted to X- and Y-coordinates. The coordinates were then integrated with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. A phenotype of advanced and more aggressive subclonal growth was present in the tumour centre, characterised by an elevated burden of somatic copy number alterations, higher necrosis, proliferation rate and Fuhrman grade. Moreover, metastasising subclones were found to 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 heightened cellular turnover and greater opportunity for driver SCNAs to arise and expand due to selective advantage. Tumour subclone growth was found to be predominantly spatially contiguous in nature, with subclone dispersal a rare event found in two cases, which notably was associated with metastasis. In terms of genetic events, 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.
- Published
- 2020
- Full Text
- View/download PDF