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The Effects of Chromosome Number on Mitotic Fidelity and Karyotype Stability

2015-05-04 00:01:09

Virginia Polytechnic Institute and State University; Dissertation; 4 May 2015



Joshua M. Nicholson



Abstract



The correct number of chromosomes is important for the maintenance of healthy cells and organisms. Maintenance of a correct chromosome number depends on the accurate distribution of chromosomes to the daughter cells during cell division, and errors in chromosome segregation result in abnormal chromosome numbers, or aneuploidy. Aneuploidy is typically associated with deleterious effects on organismal and cellular fitness; however, aneuploidy has also been associated with enhanced cellular growth in certain contexts, such as cancer. Another type of deviation from the normal chromosome number can occur when entire sets of chromosomes are added to the normal (diploid) chromosome number, resulting in polyploidy. Whereas polyploidy is found in certain normal tissues and organisms, tetraploidy (four sets of chromosomes) is associated with a number of precancerous lesions and is believed to promote aneuploidy and tumorigenesis. While it is clear that chromosome missegregation causes aneuploidy, the effect of aneuploidy on chromosome segregation is less clear. Similarly, it is unclear whether and how tetraploidy may affect chromosome segregation. The work described here shows that aneuploidy can cause chromosome missegregation and induces chromosome-specific phenotypic effects. In contrast, tetraploidy does not per seinduce chromosome missegregation, but enables the accumulation of aneuploidy thanks to a “genetic buffer” effect that allows tetraploid cells to tolerate aneuploidy better than diploid cells.



OVERVIEW



At the crux of carcinogenesis lies complexity. Amongst a single tumor, cell-to-cell variability is manifest in many different properties: karyotype, morphology, enzyme receptors, ability to metastasize, mutations, and drug resistance. While seemingly chaotic per cell, the tumor as a whole is much like a mosaic displaying interdependency and organization. For this reason, it has been called a species, a society of cells, and a complex ecosystem. It has long been known that cancer cells are characterized by aneuploid karyotypes, and an increasing body of work has unveiled a
causal relationship between aneuploidy and tumorigenesis. A key role of aneuploidy in tumorigenesis and tumor progression, is also indicated by the fact that measuring DNA indices or ploidy is
clinically informative as a prognostic indicator in various cancers. For instance, ploidy measurements in different types of cancer are as, if not more, accurate when predicting survival than other widely used measures such as the prostate-specific antigen (PSA) test.



Karyotypic analysis also indicates that there is wide variability in chromosome number within the same cancer cell population, suggesting that errors in mitotic chromosome segregation are recurrent in cancer cells. In this chapter, I review the current knowledge about intratumor karyotypic diversity, the effects of aneuploidy on cellular phenotypes, and the mechanisms that promote chromosome mis-segregation in cancer cells. In chapter two, I describe my work on the effects of aneuploidy on the fidelity of cell division. In chapter three, I describe my work on how tetraploidy influences chromosome segregation and karyotype stability. Finally, in chapter four I focus on future directions and unanswered questions.




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Key Words



aneuploidy | cancer | chromosome missegregation | tetraploidy | cytokinesis failure