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PLoS Genet. 2014 Jul 10;10(7):e1004462. doi: 10.1371/journal.pgen.1004462. eCollection 2014 Jul.

Clonal architecture of secondary acute myeloid leukemia defined by single-cell sequencing.

Author information

1
Center for Genome Sciences and Systems Biology, Washington University, St. Louis, Missouri, United States of America.
2
The Genome Institute, Washington University, St. Louis, Missouri, United States of America; Department of Genetics, Washington University, St. Louis, Missouri, United States of America.
3
The Genome Institute, Washington University, St. Louis, Missouri, United States of America.
4
Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America.
5
Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America; Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
6
The Genome Institute, Washington University, St. Louis, Missouri, United States of America; Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America.
7
Department of Genetics, Washington University, St. Louis, Missouri, United States of America; Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.
8
The Genome Institute, Washington University, St. Louis, Missouri, United States of America; Department of Genetics, Washington University, St. Louis, Missouri, United States of America; Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
9
The Genome Institute, Washington University, St. Louis, Missouri, United States of America; Department of Genetics, Washington University, St. Louis, Missouri, United States of America; Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America; Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
10
Department of Genetics, Washington University, St. Louis, Missouri, United States of America; Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America; Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America.
11
Department of Internal Medicine, Division of Oncology, Washington University, St. Louis, Missouri, United States of America; Siteman Cancer Center, Washington University, St. Louis, Missouri, United States of America; Department of Pathology and Immunology, Washington University, St. Louis, Missouri, United States of America.

Abstract

Next-generation sequencing has been used to infer the clonality of heterogeneous tumor samples. These analyses yield specific predictions-the population frequency of individual clones, their genetic composition, and their evolutionary relationships-which we set out to test by sequencing individual cells from three subjects diagnosed with secondary acute myeloid leukemia, each of whom had been previously characterized by whole genome sequencing of unfractionated tumor samples. Single-cell mutation profiling strongly supported the clonal architecture implied by the analysis of bulk material. In addition, it resolved the clonal assignment of single nucleotide variants that had been initially ambiguous and identified areas of previously unappreciated complexity. Accordingly, we find that many of the key assumptions underlying the analysis of tumor clonality by deep sequencing of unfractionated material are valid. Furthermore, we illustrate a single-cell sequencing strategy for interrogating the clonal relationships among known variants that is cost-effective, scalable, and adaptable to the analysis of both hematopoietic and solid tumors, or any heterogeneous population of cells.

PMID:
25010716
PMCID:
PMC4091781
DOI:
10.1371/journal.pgen.1004462
[Indexed for MEDLINE]
Free PMC Article
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