Oncogene-like addiction to aneuploidy in human cancers

• DOI: 10.1126/science.adg4521
• Publication Date: 2023-07-06T18:00:23Z
• Authors: Vishruth Girish; Asad A. Lakhani; Sarah L. Thompson; Christine M. Scaduto; Leanne M. Brown; Ryan A. Hagenson; Erin L. Sausville; Brianna E. Mendelson; Pranav K. Kandikuppa; Devon A. Lukow; Monet Lou Yuan; Eric C. Stevens; Sophia N. Lee; Klaske M. Schukken; Saron M. Akalu; Anand Vasudevan; Charles Zou; Barbora Salovska; Wenxue Li; Joan C. Smith; Alison M. Taylor; Robert A. Martien...; Yansheng Liu; Ruping Sun; Jason M. Sheltzer
• Keywords: Gene Editing; Carcinogenesis; Neoplasms; Proto-Oncogene Proteins; Mutation; Humans; Cell Cycle Proteins; Trisomy; Oncogenes; Tumor Suppressor Protein p53; 3. Good health

Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these “aneuploidy addictions” could be targeted as a therapeutic strategy.