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Endesfelder, D. ; Burrell, R.A.* ; Kanu, N.* ; McGranahan, N.* ; Howell, M.* ; Parker, P.J.* ; Downward, J.* ; Swanton, C.* ; Kschischo, M.*

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

Cancer Res. 74, 4853-4863 (2014)
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Expression Profiles; Colorectal-cancer; Aneuploidy; Prognosis; Survival; Cells; Metaanalysis; Subtypes; Biology; Genome
ISSN (print) / ISBN 0008-5472
e-ISSN 1538-7445
Journal Cancer Research
Quellenangaben Volume: 74, Issue: 17, Pages: 4853-4863 Article Number: , Supplement: ,
Publisher American Association for Cancer Research (AACR)
Publishing Place Philadelphia, Pa.
Reviewing status Peer reviewed