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Cancer Res. 2014 Sep 1;74(17):4853-4863. doi: 10.1158/0008-5472.CAN-13-2664. Epub 2014 Jun 26.

Chromosomal instability selects gene copy-number variants encoding core regulators of proliferation in ER+ breast cancer.

Author information

1
Department of Mathematics and Technology, RheinAhrCampus, University of Applied Sciences Koblenz, 53424 Remagen, Germany.
2
Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Institute of Biomathematics and Biometry, Scientific Computing Research Unit, Neuherberg, Germany.
3
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
4
UCL Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, WC1E 6BT London.
5
High Throughput Screening Laboratory,Cancer Research UK London Research Institute, London, United Kingdom.
6
Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
7
Division of Cancer Studies, King's College London, London SE1 1UL.
8
Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, United Kingdom.
#
Contributed equally

Abstract

Chromosomal instability (CIN) is associated with poor outcome in epithelial malignancies, including breast carcinomas. Evidence suggests that prognostic signatures in estrogen receptor-positive (ER(+)) breast cancer define tumors with CIN and high proliferative potential. Intriguingly, CIN induction in lower eukaryotic cells and human cells is context dependent, typically resulting in a proliferation disadvantage but conferring a fitness benefit under strong selection pressures. We hypothesized that CIN permits accelerated genomic evolution through the generation of diverse DNA copy-number events that may be selected during disease development. In support of this hypothesis, we found evidence for selection of gene amplification of core regulators of proliferation in CIN-associated cancer genomes. Stable DNA copy-number amplifications of the core regulators TPX2 and UBE2C were associated with expression of a gene module involved in proliferation. The module genes were enriched within prognostic signature gene sets for ER(+) breast cancer, providing a logical connection between CIN and prognostic signature expression. Our results provide a framework to decipher the impact of intratumor heterogeneity on key cancer phenotypes, and they suggest that CIN provides a permissive landscape for selection of copy-number alterations that drive cancer proliferation.

PMID:
24970479
PMCID:
PMC4167338
DOI:
10.1158/0008-5472.CAN-13-2664
[Indexed for MEDLINE]
Free PMC Article

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