Journal
CANCER RESEARCH
Volume 74, Issue 17, Pages 4853-4863Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-13-2664
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Funding
- Cancer Research UK
- EU Framework Program 7
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- MRC [G0701935] Funding Source: UKRI
- Cancer Research UK [17786, 19310, 15680, 15683] Funding Source: researchfish
- Medical Research Council [G0701935] Funding Source: researchfish
- Worldwide Cancer Research [13-0142] Funding Source: researchfish
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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) 2014 AACR.
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