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Genome Biol. 2016 Dec 9;17(1):250.

Tracing the origin of disseminated tumor cells in breast cancer using single-cell sequencing.

Author information

1
The Francis Crick Institute, London, UK.
2
Department of Human Genetics, KU Leuven-University of Leuven, Leuven, Belgium.
3
Single-cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, UK.
4
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
5
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.
6
Institute for Genomics & Systems Biology and Department of Human Genetics, University of Chicago, Chicago, IL, USA.
7
Present address: Laboratory of Genetics, University of Wisconsin, Madison, WI, USA.
8
Department of Oncology, Division of Surgery and Cancer Medicine, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
9
Present address: Department of Oncology, Akershus University Hospital, Lørenskog, Norway.
10
Department of Pathology, Oslo University Hospital, Radiumhospitalet, Oslo, Norway.
11
Present address: Department of Pediatric Research, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
12
Institute for Genomics & Systems Biology and Department of Human Genetics, University of Chicago, Chicago, IL, USA. kpwhite@uchicago.edu.
13
Tempus Labs, Chicago, IL, 60654, USA. kpwhite@uchicago.edu.
14
Department of Genetics, Institute for Cancer Research, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. v.n.kristensen@medisin.uio.no.
15
Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway. v.n.kristensen@medisin.uio.no.
16
The Francis Crick Institute, London, UK. Peter.VanLoo@crick.ac.uk.
17
Department of Human Genetics, KU Leuven-University of Leuven, Leuven, Belgium. Peter.VanLoo@crick.ac.uk.
18
Department of Human Genetics, KU Leuven-University of Leuven, Leuven, Belgium. Thierry.Voet@med.kuleuven.be.
19
Single-cell Genomics Centre, Wellcome Trust Sanger Institute, Hinxton, UK. Thierry.Voet@med.kuleuven.be.
20
Department of Oncology, Division of Surgery and Cancer Medicine, Oslo University Hospital, Radiumhospitalet, Oslo, Norway. bjorn.naume@medisin.uio.no.
21
Institute of Clinical Medicine, University of Oslo, Oslo, Norway. bjorn.naume@medisin.uio.no.

Abstract

BACKGROUND:

Single-cell micro-metastases of solid tumors often occur in the bone marrow. These disseminated tumor cells (DTCs) may resist therapy and lay dormant or progress to cause overt bone and visceral metastases. The molecular nature of DTCs remains elusive, as well as when and from where in the tumor they originate. Here, we apply single-cell sequencing to identify and trace the origin of DTCs in breast cancer.

RESULTS:

We sequence the genomes of 63 single cells isolated from six non-metastatic breast cancer patients. By comparing the cells' DNA copy number aberration (CNA) landscapes with those of the primary tumors and lymph node metastasis, we establish that 53% of the single cells morphologically classified as tumor cells are DTCs disseminating from the observed tumor. The remaining cells represent either non-aberrant "normal" cells or "aberrant cells of unknown origin" that have CNA landscapes discordant from the tumor. Further analyses suggest that the prevalence of aberrant cells of unknown origin is age-dependent and that at least a subset is hematopoietic in origin. Evolutionary reconstruction analysis of bulk tumor and DTC genomes enables ordering of CNA events in molecular pseudo-time and traced the origin of the DTCs to either the main tumor clone, primary tumor subclones, or subclones in an axillary lymph node metastasis.

CONCLUSIONS:

Single-cell sequencing of bone marrow epithelial-like cells, in parallel with intra-tumor genetic heterogeneity profiling from bulk DNA, is a powerful approach to identify and study DTCs, yielding insight into metastatic processes. A heterogeneous population of CNA-positive cells is present in the bone marrow of non-metastatic breast cancer patients, only part of which are derived from the observed tumor lineages.

KEYWORDS:

Disseminated tumor cells; Intra-tumor genetic heterogeneity; Metastasis; Phylogeny; Single-cell sequencing

Comment in

PMID:
27931250
PMCID:
PMC5146893
DOI:
10.1186/s13059-016-1109-7
[Indexed for MEDLINE]
Free PMC Article

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