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Title: Subclonal diversification of primary breast cancer revealed by multiregion sequencing

Sequencing cancer genomes may enable tailoring of therapeutics to the underlying biological abnormalities driving a particular patient's tumor. However, sequencing-based strategies rely heavily on representative sampling of tumors. To understand the subclonal structure of primary breast cancer, we applied whole-genome and targeted sequencing to multiple samples from each of 50 patients' tumors (303 samples in total). The extent of subclonal diversification varied among cases and followed spatial patterns. No strict temporal order was evident, with point mutations and rearrangements affecting the most common breast cancer genes, including PIK3CA, TP53, PTEN, BRCA2 and MYC, occurring early in some tumors and late in others. In 13 out of 50 cancers, potentially targetable mutations were subclonal. Landmarks of disease progression, such as resistance to chemotherapy and the acquisition of invasive or metastatic potential, arose within detectable subclones of antecedent lesions. These findings highlight the importance of including analyses of subclonal structure and tumor evolution in clinical trials of primary breast cancer.
Authors:
 [1] ;  [2] ;  [3] ;  [4] ;  [2] ;  [5] ;  [6] ;  [7] ;  [4] ;  [2] ;  [2] ;  [2] ;  [2] ;  [6] ;  [8] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] more »;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [9] ;  [4] ;  [9] ;  [4] ;  [9] ;  [4] ;  [4] ;  [2] ;  [4] ;  [10] ;  [3] ;  [2] ;  [2] « less
  1. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Cambridge, Cambridge (United Kingdom)
  2. Wellcome Trust Sanger Institute, Hinxton (United Kingdom)
  3. Univ. of Bergen, Bergen (Norway); Haukeland Univ. Hospital, Bergen (Norway)
  4. Univ. Libre de Bruxelles, Brussels (Belgium)
  5. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Univ. of Leuven, Leuven (Belgium)
  6. Haukeland Univ. Hospital, Bergen (Norway)
  7. Wellcome Trust Sanger Institute, Hinxton (United Kingdom); Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  8. Haukeland Univ. Hospital, Bergen (Norway); Univ. of Bergen, Bergen (Norway)
  9. Dana-Farber Cancer Institute, Boston, MA (United States)
  10. Dana-Farber Cancer Institute, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
Publication Date:
OSTI Identifier:
1236604
Report Number(s):
LA-UR--14-28200
Journal ID: ISSN 1078-8956; nm.3886
Grant/Contract Number:
AC52-06NA25396
Type:
Accepted Manuscript
Journal Name:
Nature Medicine
Additional Journal Information:
Journal Volume: 21; Journal Issue: 7; Journal ID: ISSN 1078-8956
Publisher:
Nature Publishing Group
Research Org:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES breast cancer; cancer genomics; cell migration; evolutionary genetics