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

Endesfelder, David; Burrell, Rebecca A; Kanu, Nnennaya; McGranahan, Nicholas; Howell, Mike; Parker, Peter J; Downward, Julian; ... Kschischo, Maik; + view all (2014) Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer. Cancer Research , 74 (17) pp. 4853-4863. 10.1158/0008-5472.CAN-13-2664. Green open access

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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.

Type: Article
Title: Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/0008-5472.CAN-13-2664
Publisher version: https://doi.org/10.1158/0008-5472.can-13-2664
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, EXPRESSION PROFILES, ANEUPLOIDY, SURVIVAL, PROGNOSIS, GENOME, TOOL
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10205446
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