Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq

Oncogenic driver mutations are identified in single cells by a transposon-based sequencing method. A central challenge in oncology is how to kill tumors containing heterogeneous cell populations defined by different combinations of mutated genes. Identifying these mutated genes and understanding how...

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Veröffentlicht in:Nature biotechnology 2016-09, Vol.34 (9), p.962-972
Hauptverfasser: Mann, Karen M, Newberg, Justin Y, Black, Michael A, Jones, Devin J, Amaya-Manzanares, Felipe, Guzman-Rojas, Liliana, Kodama, Takahiro, Ward, Jerrold M, Rust, Alistair G, van der Weyden, Louise, Yew, Christopher Chin Kuan, Waters, Jill L, Leung, Marco L, Rogers, Keith, Rogers, Susan M, McNoe, Leslie A, Selvanesan, Luxmanan, Navin, Nicholas, Jenkins, Nancy A, Copeland, Neal G, Mann, Michael B
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container_end_page 972
container_issue 9
container_start_page 962
container_title Nature biotechnology
container_volume 34
creator Mann, Karen M
Newberg, Justin Y
Black, Michael A
Jones, Devin J
Amaya-Manzanares, Felipe
Guzman-Rojas, Liliana
Kodama, Takahiro
Ward, Jerrold M
Rust, Alistair G
van der Weyden, Louise
Yew, Christopher Chin Kuan
Waters, Jill L
Leung, Marco L
Rogers, Keith
Rogers, Susan M
McNoe, Leslie A
Selvanesan, Luxmanan
Navin, Nicholas
Jenkins, Nancy A
Copeland, Neal G
Mann, Michael B
description Oncogenic driver mutations are identified in single cells by a transposon-based sequencing method. A central challenge in oncology is how to kill tumors containing heterogeneous cell populations defined by different combinations of mutated genes. Identifying these mutated genes and understanding how they cooperate requires single-cell analysis, but current single-cell analytic methods, such as PCR-based strategies or whole-exome sequencing, are biased, lack sequencing depth or are cost prohibitive. Transposon-based mutagenesis allows the identification of early cancer drivers, but current sequencing methods have limitations that prevent single-cell analysis. We report a liquid-phase, capture-based sequencing and bioinformatics pipeline, Sleeping Beauty (SB) capture hybridization sequencing (SBCapSeq), that facilitates sequencing of transposon insertion sites from single tumor cells in a SB mouse model of myeloid leukemia (ML). SBCapSeq analysis of just 26 cells from one tumor revealed the tumor's major clonal subpopulations, enabled detection of clonal insertion events not detected by other sequencing methods and led to the identification of dominant subclones, each containing a unique pair of interacting gene drivers along with three to six cooperating cancer genes with SB-driven expression changes.
doi_str_mv 10.1038/nbt.3637
format Article
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subjects 38/91
45/23
45/47
631/1647/334/1874/345
631/1647/514/2254
631/208/212/2305
631/67/1990/283/1897
631/67/69
64/110
64/60
Agriculture
Algorithms
Animals
Bioinformatics
Biomarkers, Tumor - genetics
Biomedical Engineering/Biotechnology
Biomedicine
Biotechnology
Cancer cells
Cells
DNA sequencing
DNA Transposable Elements
DNA, Neoplasm - genetics
Female
Gene expression
Genes, Neoplasm - genetics
Genetic aspects
Health aspects
Heterogeneity
High-Throughput Nucleotide Sequencing - methods
In Situ Hybridization - methods
Leukemia
Leukemia, Myeloid - genetics
Leukemia, Myeloid - pathology
Life Sciences
Male
Methods
Mice
Mutagenesis, Insertional - genetics
Myeloid leukemia
Neoplasm Proteins - genetics
Oncology
Sequence Analysis, DNA - methods
Software
Subpopulations
Transposases - genetics
Tumors
title Analyzing tumor heterogeneity and driver genes in single myeloid leukemia cells with SBCapSeq
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