TY  - JOUR
A1  - Endesfelder, David
A1  - Burrell, Rebecca A
A1  - Kanu, Nnennaya
A1  - McGranahan, Nicholas
A1  - Howell, Mike
A1  - Parker, Peter J
A1  - Downward, Julian
A1  - Swanton, Charles
A1  - Kschischo, Maik
PB  - AMER ASSOC CANCER RESEARCH
Y1  - 2014/09/01/
IS  - 17
JF  - Cancer Research
EP  - 4863
AV  - public
ID  - discovery10205446
SN  - 0008-5472
N1  - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions.
VL  - 74
N2  - 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.
TI  - Chromosomal instability selects gene copy number variants
encoding core regulators of proliferation in ER+ breast cancer
KW  - Science & Technology
KW  -  Life Sciences & Biomedicine
KW  -  Oncology
KW  -  EXPRESSION PROFILES
KW  -  ANEUPLOIDY
KW  -  SURVIVAL
KW  -  PROGNOSIS
KW  -  GENOME
KW  -  TOOL
UR  - https://doi.org/10.1158/0008-5472.can-13-2664
SP  - 4853
ER  -