PT - JOURNAL ARTICLE AU - Sanju Sinha AU - Karina Barbosa Guerra AU - Kuoyuan Cheng AU - Mark DM Leiserson AU - David M Wilson III AU - Bríd M. Ryan AU - Ze’ev A. Ronai AU - Joo Sang Lee AU - Aniruddha J. Deshpande AU - Eytan Ruppin TI - Integrated computational and experimental identification of <em>p53, KRAS</em> and <em>VHL</em> mutant selection associated with CRISPR-Cas9 editing AID - 10.1101/407767 DP - 2019 Jan 01 TA - bioRxiv PG - 407767 4099 - http://biorxiv.org/content/early/2019/11/02/407767.short 4100 - http://biorxiv.org/content/early/2019/11/02/407767.full AB - Recent studies have reported that CRISPR-Cas9 gene editing induces a p53-dependent DNA damage response in primary cells, which may select for cells with oncogenic p53 mutations11,12. It is unclear whether these CRISPR-induced changes are applicable to different cell types, and whether CRISPR gene editing may select for other oncogenic mutations. Addressing these questions, we analyzed genome-wide CRISPR and RNAi screens to systematically chart the mutation selection potential of CRISPR knockouts across the whole exome. Our analysis suggests that CRISPR gene editing can select for mutants of KRAS and VHL, at a level comparable to that reported for p53. These predictions were further validated in a genome-wide manner by analyzing independent CRISPR screens and patients’ tumor data. Finally, we performed a new set of pooled and arrayed CRISPR screens to evaluate the competition between CRISPR-edited isogenic p53 WT and mutant cell lines, which further validated our predictions. In summary, our study systematically charts and points to the potential selection of specific cancer driver mutations during CRISPR-Cas9 gene editing.