Aneuploidy as a promoter and suppressor of malignant growth

Vasudevan, Anand; Schukken, Klaske M.; Sausville, Erin L.; Girish, Vishruth; Adebambo, Oluwadamilare A.; Sheltzer, Jason M.

doi:10.1038/s41568-020-00321-1

Cited by 137 publications

(116 citation statements)

References 244 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…However, not all highly aneuploid cells showed increased growth (e.g., C1-06). Our data are consistent with previous reports that aneuploidy can be either tumor-promoting or tumor-suppressive 52 , 53 . Additionally, cell line CN-19 displayed no detectable aneuploidy but was the most tumorigenic (Fig.…”

Section: Resultssupporting

confidence: 93%

Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

et al. 2021

View full text Add to dashboard Cite

Abstractp53 is mutated in over half of human cancers. In addition to losing wild-type (WT) tumor-suppressive function, mutant p53 proteins are proposed to acquire gain-of-function (GOF) activity, leading to novel oncogenic phenotypes. To study mutant p53 GOF mechanisms and phenotypes, we genetically engineered non-transformed and tumor-derived WT p53 cell line models to express endogenous missense mutant p53 (R175H and R273H) or to be deficient for p53 protein (null). Characterization of the models, which initially differed only by TP53 genotype, revealed that aneuploidy frequently occurred in mutant p53-expressing cells. GOF phenotypes occurred clonally in vitro and in vivo, were independent of p53 alteration and correlated with increased aneuploidy. Further, analysis of outcome data revealed that individuals with aneuploid-high tumors displayed unfavorable prognoses, regardless of the TP53 genotype. Our results indicate that genetic variation resulting from aneuploidy accounts for the diversity of previously reported mutant p53 GOF phenotypes.

show abstract

Section: Resultssupporting

confidence: 93%

Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

et al. 2021

View full text Add to dashboard Cite

show abstract

“…It is hypothesized that aneuploidy drives tumor development by increasing the dosage of oncogenes (OGs) and decreasing the dosage of tumor suppressor genes (TSGs) 15,19,20 , which may be reflected in the recurrent aneuploid karyotypes found in certain cancer lineages 21 . Despite these findings, aneuploidy itself has also been observed to induce substantial tumor suppressive stresses 10,22,23 . Aneuploid cells have increased metabolic requirements [24][25][26][27][28][29] , display high levels of senescence 23,[30][31][32][33] , exhibit significant genomic instability 34,35 , and are sensitive to compounds that interfere with protein folding and turnover 28,[36][37][38] .…”

Section: Introductionmentioning

confidence: 99%

Extensive protein dosage compensation in aneuploid human cancers

2021

Preprint

Self Cite

View full text Add to dashboard Cite

Aneuploidy is a hallmark of human cancers, but the effects of aneuploidy on protein expression remain poorly understood. To uncover how chromosome copy number changes influence the cancer proteome, we have conducted an analysis of hundreds of human cancer cell lines with matched copy number, RNA expression, and protein expression data. We found that a majority of proteins exhibit dosage compensation and fail to change by the degree expected based on chromosome copy number alone. We uncovered a variety of gene groups that were recurrently buffered upon both chromosome gain and loss, including protein complex subunits and cell cycle genes. Several genetic and biophysical factors were predictive of protein buffering, highlighting complex post-translational regulatory mechanisms that maintain appropriate gene product dosage. Finally, we established that chromosomal aneuploidy has an unexpectedly moderate effect on the expression of oncogenes and tumor suppressors, demonstrating that these key cancer drivers can be subject to dosage compensation as well. In total, our comprehensive analysis of aneuploidy and dosage compensation across cancers will help identify the key driver genes encoded on altered chromosomes and will shed light on the overall consequences of aneuploidy during tumor development.

show abstract

“…Errors in chromosome segregation can lead to aneuploidy, the deviation in chromosome number from the diploid state. Such changes to the karyotype are associated with cancer progression, developmental disorders and ageing [1][2][3] . These pathologies are the consequence of gene dosage changes and proteomic stress 4,5 .…”

Section: Introductionmentioning

confidence: 99%

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Sen

Harrison

Burroughs

et al. 2021

Preprint

View full text Add to dashboard Cite

Chromosome mis-segregation during mitosis leads to daughter cells with deviant karyotypes (aneuploidy) and an increased mutational burden through chromothripsis of mis-segregated chromosomes. The rate of mis-segregation and the aneuploidy state are hallmarks of cancer and linked to cancer genome evolution. Errors can manifest as lagging chromosomes in anaphase, although the mechanistic origins and likelihood of correction are incompletely understood. Here we combine lattice light sheet microscopy, endogenous protein labelling and computational analysis to define the life history of >10^4 kinetochores throughout metaphase and anaphase from over 200 cells. By defining the laziness of kinetochores in anaphase, we reveal that chromosomes are at a considerable and continual risk of mis-segregation. We show that the majority of kinetochores are corrected rapidly in early anaphase through an Aurora B dependent process. Moreover, quantitative analyses of the kinetochore life histories reveal a unique dynamic signature of metaphase kinetochore oscillations that forecasts their fate in the subsequent anaphase. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with a new layer of early anaphase error correction required for stable karyotype propagation.

show abstract

Aneuploidy as a promoter and suppressor of malignant growth

Cited by 137 publications

References 244 publications

Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

Acquisition of aneuploidy drives mutant p53-associated gain-of-function phenotypes

Extensive protein dosage compensation in aneuploid human cancers

Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms

Contact Info

Product

Resources

About