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.
Preview |
Text
Endesfelder et al 2014.pdf - Published Version Download (1MB) | Preview |
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 |
Loading...
Loading...Loading...Loading...Archive Staff Only
 |
View Item |
