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Genome Biol. 2016 May 31;17(1):115. doi: 10.1186/s13059-016-0971-7.

Single-cell sequencing reveals karyotype heterogeneity in murine and human malignancies.

Author information

1
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
2
Department of Paediatrics, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
3
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, CB10 1SA, UK.
4
Department of Pathology & Medical Biology, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands.
5
Terry Fox Laboratory, BC Cancer Agency, Vancouver, BC, V5Z 1L3, Canada.
6
Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
7
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands. maria.colome@helmholtz-muenchen.de.
8
Institute of Computational Biology, Helmholtz Zentrum München, Ingolstädter Landstr. 1, Neuherberg, 85764, Germany. maria.colome@helmholtz-muenchen.de.
9
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, A. Deusinglaan 1, Groningen, 9713 AV, The Netherlands. f.foijer@umcg.nl.

Abstract

BACKGROUND:

Chromosome instability leads to aneuploidy, a state in which cells have abnormal numbers of chromosomes, and is found in two out of three cancers. In a chromosomal instable p53 deficient mouse model with accelerated lymphomagenesis, we previously observed whole chromosome copy number changes affecting all lymphoma cells. This suggests that chromosome instability is somehow suppressed in the aneuploid lymphomas or that selection for frequently lost/gained chromosomes out-competes the CIN-imposed mis-segregation.

RESULTS:

To distinguish between these explanations and to examine karyotype dynamics in chromosome instable lymphoma, we use a newly developed single-cell whole genome sequencing (scWGS) platform that provides a complete and unbiased overview of copy number variations (CNV) in individual cells. To analyse these scWGS data, we develop AneuFinder, which allows annotation of copy number changes in a fully automated fashion and quantification of CNV heterogeneity between cells. Single-cell sequencing and AneuFinder analysis reveals high levels of copy number heterogeneity in chromosome instability-driven murine T-cell lymphoma samples, indicating ongoing chromosome instability. Application of this technology to human B cell leukaemias reveals different levels of karyotype heterogeneity in these cancers.

CONCLUSION:

Our data show that even though aneuploid tumours select for particular and recurring chromosome combinations, single-cell analysis using AneuFinder reveals copy number heterogeneity. This suggests ongoing chromosome instability that other platforms fail to detect. As chromosome instability might drive tumour evolution, karyotype analysis using single-cell sequencing technology could become an essential tool for cancer treatment stratification.

KEYWORDS:

Aneuploidy; Copy number detection; Karyotype heterogeneity; Leukaemia; Lymphoma; Single-cell sequencing

PMID:
27246460
PMCID:
PMC4888588
DOI:
10.1186/s13059-016-0971-7
[Indexed for MEDLINE]
Free PMC Article

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