%V 74
%A David Endesfelder
%A Rebecca A Burrell
%A Nnennaya Kanu
%A Nicholas McGranahan
%A Mike Howell
%A Peter J Parker
%A Julian Downward
%A Charles Swanton
%A Maik Kschischo
%T Chromosomal instability selects gene copy number variants
encoding core regulators of proliferation in ER+ breast cancer
%N 17
%P 4853-4863
%D 2014
%I AMER ASSOC CANCER RESEARCH
%L discovery10205446
%J Cancer Research
%K Science & Technology, Life Sciences & Biomedicine, Oncology, EXPRESSION PROFILES, ANEUPLOIDY, SURVIVAL, PROGNOSIS, GENOME, TOOL
%X 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.
%C United States
%O This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.