Oncogene-like addiction to aneuploidy in human cancers

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 demonstrated 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 TP53 signaling, and we show that TP53 mutations are mutually-exclusive with 1q aneuploidy in human cancers. Thus, specific aneuploidies play essential roles in tumorigenesis, raising the possibility that targeting these “aneuploidy addictions” could represent a novel approach for cancer treatment. Isogenic cell lines were generated lacking recurrently observed chromosomal gains in cancer Processed RNA-Seq data used for analysis is provided for all cell lines ================================================== Submitter comment concerning missing raw data (GSM6921879-GSM6921888): Raw files for A2780 were misplaced by a former lab member during the course of this work; the lab also changed affiliations during this time -- resulting in an inability to recover raw sequencing files. However, the A2780 processed results were still used in drawing conclusions within the associated manuscript. ==================================================