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Nat Genet. 2016 Oct;48(10):1119-30. doi: 10.1038/ng.3641. Epub 2016 Aug 15.

Punctuated copy number evolution and clonal stasis in triple-negative breast cancer.

Author information

1
Department of Genetics, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
2
Graduate School of Biomedical Sciences, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
4
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
5
Peking Union Medical College, Department of Medical Oncology, Cancer Hospital and Institute, Chinese Academy of Medical Sciences, Beijing, China.
6
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
7
Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
8
Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Abstract

Aneuploidy is a hallmark of breast cancer; however, knowledge of how these complex genomic rearrangements evolve during tumorigenesis is limited. In this study, we developed a highly multiplexed single-nucleus sequencing method to investigate copy number evolution in patients with triple-negative breast cancer. We sequenced 1,000 single cells from tumors in 12 patients and identified 1-3 major clonal subpopulations in each tumor that shared a common evolutionary lineage. For each tumor, we also identified a minor subpopulation of non-clonal cells that were classified as metastable, pseudodiploid or chromazemic. Phylogenetic analysis and mathematical modeling suggest that these data are unlikely to be explained by the gradual accumulation of copy number events over time. In contrast, our data challenge the paradigm of gradual evolution, showing that the majority of copy number aberrations are acquired at the earliest stages of tumor evolution, in short punctuated bursts, followed by stable clonal expansions that form the tumor mass.

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PMID:
27526321
PMCID:
PMC5042845
DOI:
10.1038/ng.3641
[Indexed for MEDLINE]
Free PMC Article

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