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Recent studies have reported that genome editing by CRISPR–Cas9 induces a DNA damage response mediated by  p53  in primary cells hampering their growth. This could lead to a selection of cells with pre-existing  p53  mutations. In this study, employing an integrated computational and experimental framework, we systematically investigated the possibility of selection of additional cancer driver mutations during CRISPR-Cas9 gene editing. We first confirm the previous findings of the selection for pre-existing  p53  mutations by CRISPR-Cas9. We next demonstrate that similar to  p53 , wildtype  KRAS  may also hamper the growth of Cas9-edited cells, potentially conferring a selective advantage to pre-existing  KRAS -mutant cells. These selective effects are widespread, extending across cell-types and methods of CRISPR-Cas9 delivery and the strength of selection depends on the sgRNA sequence and the gene being edited. The selection for pre-existing  p53  or  KRAS  mutations may confound CRISPR-Cas9 screens in cancer cells and more importantly, calls for monitoring patients undergoing CRISPR-Cas9-based editing for clinical therapeutics for pre-existing  p53  and  KRAS  mutations.

A systematic genome-wide mapping of oncogenic mutation selection during CRISPR-Cas9 genome editing