Abstract
The evolutionary trajectories of treatment-naïve metastatic tumour are largely unknown. Such knowledge is crucial for cancer prevention and therapeutic interventions. Herein, we performed whole genome or exome sequencing of 19 tumour specimens and 8 matched normal kidney tissues from 8 clear cell renal cell carcinoma (ccRCC) patients. The clonal origin and parallel evolution of the metastatic lesions and primary tumour is identified in all 8 patients. But the evolutionary branches of primary and metastatic clones diverge early in the development of the tumour. More importantly, larger scale genomic aberrations including somatic copy number alteration (SCNA) or loss of heterozygosity (LOH) differentiate the metastasis lesions from primary tumour. Based on it, we identify that LOH at 14q, loss of 14q32.31 and gain of 6p22.2 are highly selected events during metastatic evolution. Further functional validations of multiple genes within the SCNA regions indicated that these selected events interact to drive metastatic risk with potential therapeutic relevance. Collectively, we described increased genome instability in metastatic ccRCC and validated it via molecular biology, providing an evolution pattern which may facilitate the translation of basic finding.