eprintid: 10205446 rev_number: 8 eprint_status: archive userid: 699 dir: disk0/10/20/54/46 datestamp: 2025-03-06 15:34:38 lastmod: 2025-03-06 15:34:39 status_changed: 2025-03-06 15:34:38 type: article metadata_visibility: show sword_depositor: 699 creators_name: Endesfelder, David creators_name: Burrell, Rebecca A creators_name: Kanu, Nnennaya creators_name: McGranahan, Nicholas creators_name: Howell, Mike creators_name: Parker, Peter J creators_name: Downward, Julian creators_name: Swanton, Charles creators_name: Kschischo, Maik title: Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer ispublished: pub divisions: UCL divisions: B02 divisions: C10 divisions: D19 divisions: G99 keywords: Science & Technology, Life Sciences & Biomedicine, Oncology, EXPRESSION PROFILES, ANEUPLOIDY, SURVIVAL, PROGNOSIS, GENOME, TOOL note: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. 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. date: 2014-09-01 date_type: published publisher: AMER ASSOC CANCER RESEARCH official_url: https://doi.org/10.1158/0008-5472.can-13-2664 oa_status: green full_text_type: pub language: eng primo: open primo_central: open_green verified: verified_manual elements_id: 958699 doi: 10.1158/0008-5472.CAN-13-2664 medium: Print-Electronic lyricists_name: Swanton, Robert lyricists_name: McGranahan, Nicholas lyricists_name: Kanu, Nnennaya lyricists_id: CSWAN79 lyricists_id: NLMCG29 lyricists_id: NKANU55 actors_name: Kanu, Nnennaya actors_id: NKANU55 actors_role: owner funding_acknowledgements: [Cancer Research UK]; [EU Framework Program 7]; [Prostate Cancer Foundation]; [Breast Cancer Research Foundation]; G0701935 [MRC] full_text_status: public publication: Cancer Research volume: 74 number: 17 pagerange: 4853-4863 pages: 11 event_location: United States issn: 0008-5472 citation: Endesfelder, David; Burrell, Rebecca A; Kanu, Nnennaya; McGranahan, Nicholas; Howell, Mike; Parker, Peter J; Downward, Julian; ... Kschischo, Maik; + view all <#> Endesfelder, David; Burrell, Rebecca A; Kanu, Nnennaya; McGranahan, Nicholas; Howell, Mike; Parker, Peter J; Downward, Julian; Swanton, Charles; Kschischo, Maik; - view fewer <#> (2014) Chromosomal instability selects gene copy number variants encoding core regulators of proliferation in ER+ breast cancer. Cancer Research , 74 (17) pp. 4853-4863. 10.1158/0008-5472.CAN-13-2664 <https://doi.org/10.1158/0008-5472.CAN-13-2664>. Green open access document_url: https://discovery.ucl.ac.uk/id/eprint/10205446/1/Endesfelder%20et%20al%202014.pdf