A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis

Sheltzer, J. M. (2013) A transcriptional and metabolic signature of primary aneuploidy is present in chromosomally unstable cancer cells and informs clinical prognosis. Cancer Res, 73 (21). pp. 6401-12. ISSN 1538-7445 (Electronic)0008-5472 (Linking)

URL: http://www.ncbi.nlm.nih.gov/pubmed/24041940
DOI: 10.1158/0008-5472.CAN-13-0749

Abstract

Aneuploidy is invariably associated with poor proliferation of primary cells, but the specific contributions of abnormal karyotypes to cancer, a disease characterized by aneuploidy and dysregulated proliferation, remain unclear. In this study, I demonstrate that the transcriptional alterations caused by aneuploidy in primary cells are also present in chromosomally unstable cancer cell lines, but the same alterations are not common to all aneuploid cancers. Chromosomally unstable cancer lines and aneuploid primary cells also share an increase in glycolytic and TCA cycle flux. The biological response to aneuploidy is associated with cellular stress and slow proliferation, and a 70-gene signature derived from primary aneuploid cells was defined as a strong predictor of increased survival in several cancers. Inversely, a transcriptional signature derived from clonal aneuploidy in tumors correlated with high mitotic activity and poor prognosis. Together, these findings suggested that there are two types of aneuploidy in cancer: one is clonal aneuploidy, which is selected during tumor evolution and associated with robust growth, and the other is subclonal aneuploidy caused by chromosomal instability (CIN). Subclonal aneuploidy more closely resembles the stressed state of primary aneuploid cells, yet CIN is not benign; a subset of genes upregulated in high-CIN cancers predict aggressive disease in human patients in a proliferation-independent manner.

Item Type: Paper
Uncontrolled Keywords: *Aneuploidy Cell Transformation, Neoplastic/*pathology Cells, Cultured Chromosomal Instability/*genetics Embryo, Mammalian/cytology/*metabolism Female Fibroblasts/cytology/*metabolism *Gene Expression Profiling Humans Neoplasms/*genetics/pathology Oligonucleotide Array Sequence Analysis Prognosis Tumor Markers, Biological/*genetics/metabolism
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal duplications > aneuploidy
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > chromosomal duplications
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > gene expression
CSHL Authors:
Communities: CSHL labs > Sheltzer lab
Depositing User: Matt Covey
Date Deposited: 10 Sep 2015 16:59
Last Modified: 10 Sep 2015 16:59
PMCID: PMC3901577
Related URLs:
URI: http://repository.cshl.edu/id/eprint/31746

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