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

Abstract

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.

• Authors: Sanju Sinha, Karina Barbosa, Kuoyuan Cheng, Mark D M Leiserson, Prashant Jain, Anagha Deshpande, David M Wilson 3rd, Bríd M Ryan, Ji Luo, Ze'ev A Ronai, Joo Sang Lee, Aniruddha J Deshpande, Eytan Ruppin
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6512 (11 11 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34764240 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• KRAS protein, human
• CRISPR-Associated Protein 9
• Proto-Oncogene Proteins p21(ras)

Topics

• CRISPR-Associated Protein 9 (genetics, metabolism)
• Computational Biology
• Gene Editing (methods)
• Humans
• Mutation (genetics)
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)