The aneuploidy paradox: costs and benefits of an incorrect karyotype

Sheltzer, Jason M.; Amon, Angelika

doi:10.1016/j.tig.2011.07.003

Cited by 216 publications

(238 citation statements)

References 106 publications

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“…UW473 cells were relatively more sensitive to CDDP, MTX, and TMZ treatments and more resistant to DX than UW402 cell line. Although it has been largely described that CIN confers intrinsic multidrug resistance in tumors (Sheltzer and Amon 2011;Lee et al 2011) and consequently poorer prognosis in cancer patients (Carter et al 2006), in our study, UW473 showed a greater CIN phenotype and it was more chemosensitivity than UW402, which could confirm the hypothesis that excessive genomic instability may surpass a threshold compatible with cell viability (Cahill et al 1999). This concept has been recently corroborated in the clinical context through studies reporting a paradoxical relationship between CIN and survival outcome in cancer, being that tumors exhibiting extreme CIN displayed improved prognosis relative to tumors with intermediate levels of CIN Roylance et al 2011;McGranahan et al 2012;Lee and Swanton 2012).…”

Section: Discussionsupporting

confidence: 77%

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Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

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Chromosomal heterogeneity is a hallmark of most tumors and it can drive critical events as growth advantages, survival advantages, progression and karyotypic evolution. Medulloblastoma (MB) is the most common malignant central nervous system tumor in children. This work attempted to investigate chromosomal heterogeneity and instability profiles of two MB pediatric cell lines and their relationship with cell phenotype. We performed GTG-banding and cytokinesis-block micronucleus cytome assays, as well as morphological characterization, cell population doubling time, colony-forming efficiency, and chemo-sensitivity assays in two pediatric MB cell lines (UW402 and UW473). Both MB cells showed a high chromosomal heterogeneity. UW473 cells showed *2 fold higher both clonal-and non-clonal chromosomal alterations than UW402 cells. Besides, UW473 showed two clonal-groups well-differentiated by ploidy level (\2n[and\4n[) and also presented a significantly higher number of chromosomal instability biomarkers. These results were associated with high morphological heterogeneity and survival advantages for UW473 and proliferation advantages for UW402 cells. Moreover, UW473 was significantly more sensitive to methotrexate, temozolomide and cisplatin while UW402 cells were more sensitive to doxorubicin. These data suggest that distinct different degrees of karyotypic heterogeneity and instability may affect neoplasic phenotype of MB cells. These findings bring new insights into cell and tumor biology.

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Section: Discussionsupporting

confidence: 77%

“…Aneuploidy and CIN contribute for the chromosomal heterogeneity in tumor cells (Sheltzer and Amon 2011;Gordon et al 2012). Here, we found not only highly complex aneuploidy, but also CIN phenotype investigated by CBMN-Cyt assay.…”

Section: Discussionmentioning

confidence: 54%

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

et al. 2013

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“…Although the RUD events are rare (∼10 −7 /division), they are similar in frequency to other classes of mitotic genetic rearrangements (i.e., reciprocal crossovers and chromosome loss) in WT yeast strains. Because most aneuploid cells have a substantial growth disadvantage compared with euploid cells (19), an advantage of RUD as a pathway for producing UPD compared with the pathways diagrammed in Fig. 1B is the lack of aneuploid intermediate formation.…”

Section: Discussionmentioning

confidence: 99%

Reciprocal uniparental disomy in yeast

Andersen

Petes

2012

Proc. Natl. Acad. Sci. U.S.A.

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In the diploid cells of most organisms, including humans, each chromosome is usually distinguishable from its partner homolog by multiple single-nucleotide polymorphisms. One common type of genetic alteration observed in tumor cells is uniparental disomy (UPD), in which a pair of homologous chromosomes are derived from a single parent, resulting in loss of heterozygosity for all single-nucleotide polymorphisms while maintaining diploidy. Somatic UPD events are usually explained as reflecting two consecutive nondisjunction events. Here we report a previously undescribed mode of chromosome segregation in Saccharomyces cerevisiae in which one cell division produces daughter cells with reciprocal UPD for the same pair of chromosomes without an aneuploid intermediate. One pair of sister chromatids is segregated into one daughter cell and the other pair is segregated into the other daughter cell, mimicking a meiotic chromosome segregation pattern. We term this process “reciprocal uniparental disomy.”

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“…Duplication of particular chromosomes (i.e., aneuploidy) creates, in addition, a stoichiometric imbalance between gene products (14,15) and promotes further genome destabilizing events (16,17). Thus, it appears that aneuploidy is concurrently advantageous and highly costly (18,19). Therefore, it is not clear under what conditions and to what extent organisms will adopt this solution.…”

mentioning

confidence: 99%

Chromosomal duplication is a transient evolutionary solution to stress

Yona

Manor

Herbst

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

319

373

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Aneuploidy, an abnormal number of chromosomes, is a widespread phenomenon found in unicellulars such as yeast, as well as in plants and in mammalians, especially in cancer. Aneuploidy is a genomescale aberration that imposes a severe burden on the cell, yet under stressful conditions specific aneuploidies confer a selective advantage. This dual nature of aneuploidy raises the question of whether it can serve as a stable and sustainable evolutionary adaptation. To clarify this, we conducted a set of laboratory evolution experiments in yeast and followed the long-term dynamics of aneuploidy under diverse conditions. Here we show that chromosomal duplications are first acquired as a crude solution to stress, yet only as transient solutions that are eliminated and replaced by more efficient solutions obtained at the individual gene level. These transient dynamics of aneuploidy were repeatedly observed in our laboratory evolution experiments; chromosomal duplications gained under stress were eliminated not only when the stress was relieved, but even if it persisted. Furthermore, when stress was applied gradually rather than abruptly, alternative solutions appear to have emerged, but not aneuploidy. Our findings indicate that chromosomal duplication is a first evolutionary line of defense, that retains survivability under strong and abrupt selective pressures, yet it merely serves as a "quick fix," whereas more refined and sustainable solutions take over. Thus, in the perspective of genome evolution trajectory, aneuploidy is a useful yet short-lived intermediate that facilitates further adaptation.evolutionary dynamics | environmental stress | heat tolerance | pH tolerance

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The aneuploidy paradox: costs and benefits of an incorrect karyotype

Cited by 216 publications

References 106 publications

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Chromosomal heterogeneity and instability characterize pediatric medulloblastoma cell lines and affect neoplastic phenotype

Reciprocal uniparental disomy in yeast

Chromosomal duplication is a transient evolutionary solution to stress

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