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

Sanju Sinha, Karina Barbosa, Kuoyuan Cheng, Mark D.M. Leiserson, Prashant Jain, Anagha Deshpande, David M. Wilson, Bríd M. Ryan, Ji Luo, Ze’ev A. Ronai, Joo Sang Lee, Aniruddha J. Deshpande, Eytan Ruppin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number6512
JournalNature Communications
Issue number1
StatePublished - Dec 2021
Externally publishedYes


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