Human Tumor Cells Display an Oncogene-like Addiction to Aneuploidy

Alterations in chromosome copy number, or aneuploidy, are common features of human cancers. Despite its prevalence across tumor genomes, the functional importance of aneuploidy to tumor­igenesis is poorly understood. In this study, Girish, Lakhani, and colleagues utilized CRISPR-based genome editing tools entitled ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting) to restore disomy in aneuploidy-containing cells in order to functionally interrogate cancer aneuploidies. Analysis of sequencing data from several cancer types revealed that aneuploidy events occur early in cancer progression, indicating that aneuploidy may promote tumor fitness and development. Moreover, gains of specific chromosomes were enriched across cancer types, including trisomy of chromosome 1q, which was associated with poor patient outcomes and was mutually exclusive with loss of the tumor suppressor gene TP53. CRISPR-induced loss of trisomy 1q in a number of human cancer cell lines significantly reduced anchorage-independent growth as well as subcutaneous tumor xenograft growth. Other enriched aneuploidy events, including 7q and 8q trisomy, exhibited less severe malignant phenotypes, suggesting that tumor cells exhibit different degrees of addiction to unique aneuploidies. In an immortal but nontumorigenic cell line, loss of trisomy 1q blocked oncogene expression–induced malignant transformation. Additionally, ablation of aneuploidy induced a selective pressure on tumor cells to regain 1q trisomy, reflected by restored trisomy in xenograft tumors or upon prolonged passaging in culture. Mechanistically, chromosome 1q gain induced expression of the 1q-encoded MDM4 gene, which repressed p53 transcriptional activity to promote malignancy in 1q-trisomic cells. Induction of BLX9, a p53-independent, 1q-encoded gene, was also functionally important for aneuploidy-induced malignant phenotypes. Finally, the 1q-encoded UCK2 gene, which controls the activation of toxic nucleotide analogues, rendered 1q-trisomic cells particularly sensitive to UCK2-dependent nucleotide analogues. In conclusion, this study revealed that human cancers display an oncogene-like addiction to specific aneuploidy events, which may create therapeutically actionable collateral vulnerabilities.

Girish V, Lakhani AA, Thompson SL, Scaduto CM, Brown LM, Hagenson RA, et al. Oncogene-like addiction to aneuploidy in human cancers. Science 2023 Jul 6 [Epub ahead of print].

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.