Aneuploidy Drives Genomic Instability in Yeast

David H. Koch Institute for Integrative Cancer Research and Howard Hughes Medical Institute (HHMI), Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Science (Impact Factor: 33.61). 08/2011; 333(6045):1026-30. DOI: 10.1126/science.1206412
Source: PubMed


Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity.
To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy
on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all
aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and
mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic
recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant
growth in cancer.

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    • "While we were unable to classify these two groups based on gene expression differences, we did identify a list of 98 genes from across the genome all down-regulated in the chromosome 1q samples versus wild type. Aneuploidy work in yeast has shown that copy number alterations of chromosome arms can effect gene expression globally and is not limited to genes on the effected chromosome [31,32]. Our preliminary results here also indicate that the gain of chromosome 1q may have global effects on gene expression, and given its prevalence in early neoplasias associated with cancer, it may be important for the earliest stages of cancer development. "
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    ABSTRACT: Background The earliest recognizable stages of breast neoplasia are lesions that represent a heterogeneous collection of epithelial proliferations currently classified based on morphology. Their role in the development of breast cancer is not well understood but insight into the critical events at this early stage will improve efforts in breast cancer detection and prevention. These microscopic lesions are technically difficult to study so very little is known about their molecular alterations. Results To characterize the transcriptional changes of early breast neoplasia, we sequenced 3′- end enriched RNAseq libraries from formalin-fixed paraffin-embedded tissue of early neoplasia samples and matched normal breast and carcinoma samples from 25 patients. We find that gene expression patterns within early neoplasias are distinct from both normal and breast cancer patterns and identify a pattern of pro-oncogenic changes, including elevated transcription of ERBB2, FOXA1, and GATA3 at this early stage. We validate these findings on a second independent gene expression profile data set generated by whole transcriptome sequencing. Measurements of protein expression by immunohistochemistry on an independent set of early neoplasias confirms that ER pathway regulators FOXA1 and GATA3, as well as ER itself, are consistently upregulated at this early stage. The early neoplasia samples also demonstrate coordinated changes in long non-coding RNA expression and microenvironment stromal gene expression patterns. Conclusions This study is the first examination of global gene expression in early breast neoplasia, and the genes identified here represent candidate participants in the earliest molecular events in the development of breast cancer.
    Full-text · Article · May 2014 · Genome Biology
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    • "DNA repair is significantly downregulated, which might lead to increased accumulation of DNA damage. The abundance changes in the DNA replication and repair factors might explain how aneuploidy increases genome instability, as has been observed in yeast [4] as well as in human aneuploids (S.S., V.P., Z.S., unpublished results). Further research should elucidate what are the causes of the consistent downregulation of DNA metabolism pathways and what consequences it brings upon aneuploid cells. "
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    ABSTRACT: Aneuploidy, a karyotype deviating from multiples of a haploid chromosome set, affects the physiology of eukaryotes. In humans, aneuploidy is linked to pathological defects such as developmental abnormalities, mental retardation or cancer, but the underlying mechanisms remain elusive. There are many different types and origins of aneuploidy, but whether there is a uniform cellular response to aneuploidy in human cells has not been addressed so far. Here we evaluate the transcription profiles of eleven trisomic and tetrasomic cell lines and two cell lines with complex aneuploid karyotypes. We identify a characteristic aneuploidy response pattern defined by upregulation of genes linked to endoplasmic reticulum, Golgi apparatus and lysosomes, and downregulation of DNA replication, transcription as well as ribosomes. Strikingly, complex aneuploidy elicits the same transcriptional changes as trisomy. To uncover the triggers of the response, we compared the profiles with transcription changes in human cells subjected to stress conditions. Interestingly, we found an overlap only with the response to treatment with the autophagy inhibitor bafilomycin A1. Finally, we identified 23 genes whose expression is significantly altered in all aneuploids and which may thus serve as aneuploidy markers. Our analysis shows that despite the variability in chromosome content, aneuploidy triggers uniform transcriptional response in human cells. A common response independent of the type of aneuploidy might be exploited as a novel target for cancer therapy. Moreover, the potential aneuploidy markers identified in our analysis might represent novel biomarkers to assess the malignant potential of a tumor.
    Full-text · Article · Feb 2014 · BMC Genomics
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    • "Such mutations represent an adaptive response to adverse effects of random aneuploidies. Since aneuploidy lead to increased mutational rate and structural genome instability, acquisition of adaptive changes might be accelerated by aneuploidy-induced genomic instability (113). "
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    Full-text · Article · Dec 2013 · Frontiers in Oncology
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