TY - JOUR 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. ID - discovery10205446 UR - https://doi.org/10.1158/0008-5472.can-13-2664 Y1 - 2014/09/01/ JF - Cancer Research 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 VL - 74 SP - 4853 IS - 17 EP - 4863 SN - 0008-5472 TI - Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer AV - public KW - Science & Technology KW - Life Sciences & Biomedicine KW - Oncology KW - EXPRESSION PROFILES KW - ANEUPLOIDY KW - SURVIVAL KW - PROGNOSIS KW - GENOME KW - TOOL N1 - This version is the author accepted manuscript. For information on re-use, please refer to the publisher?s terms and conditions. ER -