Tetraploidy in cancer: Diagnostic and therapeutic perspectives

Tetraploidy, defined as a cell state containing four complete sets of chromosomes, is a major event in cancer development and progression. This review first presents the mechanisms of formation of tetraploid cells that involve five main pathways: endoreduplication bypass, DNA re-replication, telomeric crisis, failure of cytokinesis and post-mitotic survival, all regulated by key molecular players including p53, Rb1 and cyclins. While transient tetraploidy occurs in some physiological contexts, its persistence leads to chromosomal instability, generating numerical and structural aberrations that feed tumor heterogeneity and evolution. Next, we review the interactions between tetraploidy and the various hallmarks of cancer, organized according to their primary role in one of the fundamental processes of the tumor cell: differentiation, proliferation, survival, adaptation, and dissemination. The review then focuses on the interests of tetraploidy as a predictive diagnostic element regarding, on one hand, the risk of malignant transformation and, on the other hand, for acquired tumors, the severity of these in terms of growth rate, metastatic dissemination and resistance to treatments. Finally, pharmacological avenues based on tetraploidy are presented and discussed, taking into account that tetraploidy presents a therapeutic duality: anti-tetraploidy strategies that aim to prevent the formation or survival of tetraploid cells, while pro-tetraploidy approaches exploit the inherent fragility of genomically doubled cells to induce mitotic catastrophe. Understanding the molecular mechanisms governing tetraploidy and its micro-environmental interactions offers opportunities for precision oncology, enabling risk stratification, early detection and targeted interventions.