Whole-genome doubling in tissues and tumors

• Published in: Trends in genetics 2023-12, Vol.39 (12), p.954-967
• Main Authors: Vittoria, Marc A., Quinton, Ryan J., Ganem, Neil J.
• Format: Article
• Language: English
• Subjects: binucleate; Cell Division; Cell Physiological Phenomena; CIN; Genome - genetics; Humans; KIF18A; Neoplasms - genetics; polyploid; tetraploid; Tetraploidy; whole-genome doubling
• ISSN: 0168-9525
• DOI: 10.1016/j.tig.2023.08.004

Unscheduled whole-genome doubling (WGD) events give rise to tetraploid cells that are prone to replication-stress-induced DNA damage, chromosome instability, and oncogenic epigenetic alterations.Proliferating whole-genome doubled cells are tumorigenic and comprise ∼37% of primary and ∼56% of metastatic solid tumors.Whole-genome doubled cancer cells must acquire specific genetic and physiological adaptations to accommodate the unique stresses imposed by their doubled DNA and cellular content.Identifying genes that are essential for the viability of proliferating whole-genome doubled cancer cells, yet dispensable for the viability of diploid cells (i.e., ploidy-specific lethal genes), has the potential to uncover new cancer therapeutics. The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD+) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD+ cells. The overwhelming majority of proliferating somatic human cells are diploid, and this genomic state is typically maintained across successive cell divisions. However, failures in cell division can induce a whole-genome doubling (WGD) event, in which diploid cells transition to a tetraploid state. While some WGDs are developmentally programmed to produce nonproliferative tetraploid cells with specific cellular functions, unscheduled WGDs can be catastrophic: erroneously arising tetraploid cells are ill-equipped to cope with their doubled cellular and chromosomal content and quickly become genomically unstable and tumorigenic. Deciphering the genetics that underlie the genesis, physiology, and evolution of whole-genome doubled (WGD+) cells may therefore reveal therapeutic avenues to selectively eliminate pathological WGD+ cells.