Multiple other studies have suggested non-mutation related reasons as to why a ccRCC tumour metastasises, including expression, protein, and epigenetic changes.15–17 However, there is emerging evidence that specific mutations in advanced RCC may increase over subsequent lines of therapy.14 One study of circulating free DNA from RCC patients showed increasing TP53 and mTOR pathway elements (e.g., NF1, PIK3CA) alterations after first-line vascular endothelial growth factor-directed therapy. This evidence concerns the gene NF1 and neoplasm.