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.
Highlights
Clear cell renal cell carcinoma has a well described evolutionary basis, with loss of chromosome 3p and inactivation of VHL representing pathognomonic features of the disease[1,2,3,4]
Somatic copy number alteration burden, necrosis and pathological grade are higher at the tumour centre
A key finding from this work is that metastatic Clear cell renal cell carcinoma (ccRCC) subclones preferentially originate from the interior of the tumour rather than the margin, with the tumour centre characterised by higher levels of proliferation, necrosis, Fuhrman grade and somatic copy number alteration (SCNA) burden
Summary
Clear cell renal cell carcinoma (ccRCC) has a well described evolutionary basis, with loss of chromosome 3p and inactivation of VHL representing pathognomonic features of the disease[1,2,3,4] These founding clonal events are classically followed by acquisition of widespread intratumour heterogeneity, which is characterised by the accrual of additional subclonal genetic alteration(s) including SETD2, PBRM1 and BAP1 mutation, and/or somatic copy number loss of chromosome arms including 14q and 9p5,6. This defined sequence of events, coupled with a general lack of extreme mutagenesis[7] and strong evidence of selection[8], renders ccRCC an excellent model for exploring the principles of tumour evolution. In order to achieve a more complete understanding of cancer evolution within its natural ecological context[11], spatially and genomic resolved analyses of clinical cohorts are urgently required
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