Whole-Genome Doubling as a source of cancer: how, when, where, and why?

Abstract

Chromosome instability is a well-known hallmark of cancer, leading to increased genetic plasticity of tumoral cells, which favors cancer aggressiveness, and poor prognosis. One of the main sources of chromosomal instability are events that lead to a Whole-Genome Duplication (WGD) and the subsequently generated cell polyploidy. In recent years, several studies showed that WGD occurs at the early stages of cell transformation, which allows cells to later become aneuploid, thus leading to cancer progression. On the other hand, other studies convey that polyploidy plays a tumor suppressor role, by inducing cell cycle arrest, cell senescence, apoptosis, and even prompting cell differentiation, depending on the tissue cell type. There is still a gap in understanding how cells that underwent WGD can overcome the deleterious effect on cell fitness and evolve to become tumoral. Some laboratories in the chromosomal instability field recently explored this paradox, finding biomarkers that modulate polyploid cells to become oncogenic. This review brings a historical view of how WGD and polyploidy impact cell fitness and cancer progression, and bring together the last studies that describe the genes helping cells to adapt to polyploidy.

The two sides of chromosomal instability: drivers and brakes in cancer

“…108,237,238 Endoreduplication is a process in which cells undergo multiple rounds of DNA replication without mitosis, resulting in cells with multiple copies of their genome. 239 Endoreduplication can occur due to various reasons, such as problems with the cell cycle machinery. 239 One key cell cycle machinery associated with this endoreduplication is a defect in the pre-replication complex (pre-RC).…”

“…239 Endoreduplication can occur due to various reasons, such as problems with the cell cycle machinery. 239 One key cell cycle machinery associated with this endoreduplication is a defect in the pre-replication complex (pre-RC). 240 The pre-RC, which includes the origin recognition complex, cell division cycle 6, chromatin licensing and DNA replication factor 1 (CDT1), and minichromosome maintenance complex 2-7, assembles at replication origins during G1 phase to license DNA replication at S phase.…”

“…228,[241][242][243][244][245][246] Cell fusion is a process in which two or more cells fuse together to form a single cell with multiple nuclei, also known as a synkaryote. 239,247 This can occur due to various reasons, such as exposure to certain viruses or chemicals. 239,247 Following fusion, the parental chromosomes mix and redistribute to the fused cells, thereby producing polyploid fused cells.…”

“…239,247 This can occur due to various reasons, such as exposure to certain viruses or chemicals. 239,247 Following fusion, the parental chromosomes mix and redistribute to the fused cells, thereby producing polyploid fused cells. 239,247 Therefore, cell fusion can also result in polyploid cells and contribute to CIN.…”

CDK4/6 activity is required during G 2 arrest to prevent stress-induced endoreplication

“…WGD can occur through cell fusion, mitotic failure, or endocycling (i.e., two consecutive S-phase rounds without mitosis) ( 4 ). A critical step in endocycling is the decoupling of mitosis from relicensing of the replication origins, which are normally coupled through activation of the anaphase-promoting complex or cyclosome (APC/C) at mitosis ( 5 , 6 ).…”