For most common cancers, we will soon know the full complement of driver mutations that occur at a ‘reasonable’ frequency (for example, in at least 1% of tumors), and all early indicators suggest that this number will not be more than 100–200 genes at most. Targeted sequencing of this limited number of genes will be relatively simple, and, moreover, can be done at great depth, which will enable the identification of all subclones, even minor ones. A greater challenge will be to determine how to sample multiple sites that might be very heterogeneous and how this will influence targeted therapies. If the ‘actionable mutation’ is present in the founding clone, then only one site will have to be biopsied, but mutations unique to particular sites will of course imply more biopsies. Finally, clonal heterogeneity
suggests that combinations of targeted therapies will be more effective, and we can anticipate