Aneuploidy: Cancer strength or vulnerability?

Abstract

Aneuploidy is a very rare and tissue-specific event in normal conditions, occurring in a low number of brain and liver cells. Its frequency increases in age-related disorders and is one of the hallmarks of cancer. Aneuploidy has been associated with defects in the spindle assembly checkpoint (SAC). However, the relationship between chromosome number alterations, SAC genes and tumor susceptibility remains unclear. Here, we provide a comprehensive review of SAC gene alterations at genomic and transcriptional level across human cancers and discuss the oncogenic and tumor suppressor functions of aneuploidy. SAC genes are rarely mutated but frequently overexpressed, with a negative prognostic impact on different tumor types. Both increased and decreased SAC gene expression show oncogenic potential in mice. SAC gene upregulation may drive aneuploidization and tumorigenesis through mitotic delay, coupled with additional oncogenic functions outside mitosis. The genomic background and environmental conditions influence the fate of aneuploid cells. Aneuploidy reduces cellular fitness. It induces growth and contact inhibition, mitotic and proteotoxic stress, cell senescence and production of reactive oxygen species. However, aneuploidy confers an evolutionary flexibility by favoring genome and chromosome instability (CIN), cellular adaptation, stem cell-like properties and immune escape. These properties represent the driving force of aneuploid cancers, especially under conditions of stress and pharmacological pressure, and are currently under investigation as potential therapeutic targets. Indeed, promising results have been obtained from synthetic lethal combinations exploiting CIN, mitotic defects, and aneuploidy-tolerating mechanisms as cancer vulnerability.

Tissue specific vulnerability to mitotic defects caused by mutations in theDrosophilaASPM homologue, Asp

“…This developmental stage coincides with increased mitosis after a period of dormancy (Poulton et al 2017). Mitotic errors can lead to aneuploidy, which is well tolerated in mammalian and insect neural progenitors (Damiani et al 2016;Poulton et al 2017) but may be associated with tumourigenesis in other cell types (Simonetti et al 2019). Cells that cannot force mitotic completion in this way can either exit the cell cycle as a 4N cell or enter apoptosis.…”

Combination of the Hansemann-Boveri, Warburg, and Knudson Theories of Cancer, Based on Failure of Missegregation Damage Mitigation

“…The most common missegregation is when one daughter cell gets an extra chromosome and the other gets one chromosome less than normal. This can happen in several ways [23,24]; One is via non-disjunction, where sister chromatids fail to separate and move together to one pole. Another is when a lagging chromosome fails to be incorporated into the new nucleus; instead, it may form a micronucleus, with its own nuclear membrane.…”

Evolution of Cancer Progression in the Context of Darwinism

“…However, the failure of the mitotic apparatus or chromosomal structure or function can cause aneuploidy. Although present in normal tissue, aneuploid cells are genetically abnormal and frequently associated with many types of cancer including breast, lung, prostatic, lung and ovarian, and glioblastoma (46)(47)(48)(49). Of note, aneuploidy, mainly tetraploidy, frequently observed in cancer also seems to be associated with ageing (50) and also plays a certain role in stem cell biology (51).…”