Single-chromosome Gains Commonly Function as Tumor Suppressors

Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as...

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Bibliographic Details
Published in:Cancer cell 2017-02, Vol.31 (2), p.240-255
Main Authors: Sheltzer, Jason M., Ko, Julie H., Replogle, John M., Habibe Burgos, Nicole C., Chung, Erica S., Meehl, Colleen M., Sayles, Nicole M., Passerini, Verena, Storchova, Zuzana, Amon, Angelika
Format: Article
Language:English
Subjects:
Aneuploidy
Animals
Cell Proliferation
Cell Transformation, Neoplastic
chromosomal instability
Chromosome Aberrations
Genes, ras
genome dosage imbalance
Genomic Instability
HCT116 Cells
Humans
Neoplasms - genetics
Neoplasms - prevention & control
Oncogenes
transformation
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Summary:Aneuploidy is a hallmark of cancer, although its effects on tumorigenesis are unclear. Here, we investigated the relationship between aneuploidy and cancer development using cells engineered to harbor single extra chromosomes. We found that nearly all trisomic cell lines grew poorly in vitro and as xenografts, relative to genetically matched euploid cells. Moreover, the activation of several oncogenic pathways failed to alleviate the fitness defect induced by aneuploidy. However, following prolonged growth, trisomic cells acquired additional chromosomal alterations that were largely absent from their euploid counterparts and that correlated with improved fitness. Thus, while single-chromosome gains can suppress transformation, the genome-destabilizing effects of aneuploidy confer an evolutionary flexibility that may contribute to the aggressive growth of advanced malignancies with complex karyotypes. •Single-chromosome gains inhibit anchorage-independent growth and xenograft formation•P53 loss and Ras activation fail to normalize the fitness of trisomic cells•Trisomic cells acquire additional karyotype changes during prolonged growth•Trisomic cells can evolve over time to a higher-fitness state By analyzing genetically matched euploid and trisomic cells, Sheltzer et al. find that single-chromosome gains commonly suppress tumorigenicity, and the tumor-suppressive effects of aneuploidy cannot be fully overcome by introducing oncogenic mutations. Following prolonged growth, trisomic cells acquire additional karyotype changes with improved fitness.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccell.2016.12.004