Trisomy Formation Within Cancers

by Annabelle Shilling (IV)

Trisomies are the most common cancerous chromosomal abnormalities. As a result, many researchers have attempted to identify how they form. Many consider a dysfunctional spindle assembly checkpoint (SAC) to be the cause of such errors, implying that the improper separation of sister chromatids during mitosis causes the gain of an extra chromosome in some cells; however, researchers studying the childhood kidney cancer nephroblastoma have discovered evidence suggesting otherwise. Tripolar mitosis is often a distinguishing feature of cancerous tissue. Because bipolar mitosis is the default for many healthy cells, tripolar mitosis, a mitotic division creating three daughter cells instead of two, is a dangerous abnormality (Figure 1). Bipolar mitosis requires two centrosomes to be active, but any quantity greater than two can result in undesired spindle poles. These spindle poles guide the chromosomes to different parts of the cell for replication (anaphase), but when there are three of them active rather than two, the chromosomes are pulled in three different directions. Thus, the cell is preparing to split the chromosomal content into three daughter cells.

Nephroblastoma models used by researchers at Lund University demonstrated that it is possible for trisomies to form even when the SAC is functional. This formation is possible when triple mitosis begins to occur but fails during cytokinesis, resulting in the production of two cells but with a mismatch in chromosome counts. Multipolar divisions are 16 to 128 times more likely to result in chromosomal aberrations than bipolar segregation errors, and of the 18 initial cells involved in the study that exhibited tripolar mitosis, only two did not fail during cytokinesis. Researchers later found, using a different set of cells, that 80% of tripolar replications fail during cytokinesis, in contrast to a mere 5% of bipolar replications. These failures in cytokinesis often lead to trisomies in the subsequent binucleated daughter cells. Contrary to popular belief, mutations present in genes involved in the mitotic checkpoint are uncommon in human cancers, thus further debunking the SAC theory. That being said, it is not yet certain how epigenetic components affect this process, so the lack of mutations cannot be taken as complete evidence. The mechanisms through which cancer is induced are very complex, and there is no standard to be applied to cancer as a whole. Tripolar mitosis has not been proven to cause all trisomies in cancers, and the research discussed above simply discredits the common assumption that the SAC is solely responsible for those trisomies.

Figure 1: Tripolar mitosis

Works Cited

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Rahman, N., Mertens, F., Mitelman, F., & Mandahl, N. (2010). Generation of trisomies in cancer cells by multipolar mitosis and incomplete cytokinesis. Proceedings of the National Academy of Sciences, 107(47), 20489-20493. https://doi.org/10.1073/pnas.1006829107

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T., Summers, M. C., & Handyside, A. H. (2017). Tripolar mitosis and partitioning of the genome arrests human preimplantation development in vitro. Scientific Reports, 7(1). https://doi.org/10.1038/s41598-017-09693-1

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