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Nat Med. 2015 Jul;21(7):751-9. doi: 10.1038/nm.3886. Epub 2015 Jun 22.

Subclonal diversification of primary breast cancer revealed by multiregion sequencing.

Author information

1
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Oncology, The University of Cambridge, Cambridge, UK.
2
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
3
1] Section of Oncology, Department of Clinical Science, University of Bergen, Bergen, Norway. [2] Department of Oncology, Haukeland University Hospital, Bergen, Norway.
4
Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium.
5
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Department of Human Genetics, University of Leuven, Leuven, Belgium.
6
Department of Surgery, Haukeland University Hospital, Bergen, Norway.
7
1] Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK. [2] Theoretical Division, Los Alamos National Laboratory, Los Alamos, New Mexico, USA.
8
Department of Pathology, Haukeland University Hospital, Bergen, Norway.
9
1] Department of Pathology, Haukeland University Hospital, Bergen, Norway. [2] The Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
10
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
11
1] Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

The sequencing of 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.

PMID:
26099045
PMCID:
PMC4500826
DOI:
10.1038/nm.3886
[Indexed for MEDLINE]
Free PMC Article

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