Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 50, Pages 17947-17952Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1420822111
Keywords
single-cell genomics; acute lymphoblastic leukemia; intratumor heterogeneity; clonal evolution; cytosine mutagenesis
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Funding
- American Society of Hematology
- Leukemia and Lymphoma Society
- Spectrum Child Health Research Institute at Stanford
- A*STAR, agency of science, technology and research, Singapore
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Many cancers have substantial genomic heterogeneity within a given tumor, and to fully understand that diversity requires the ability to perform single cell analysis. We performed targeted sequencing of a panel of single nucleotide variants (SNVs), deletions, and IgH sequences in 1,479 single tumor cells from six acute lymphoblastic leukemia (ALL) patients. By accurately segregating groups of cooccurring mutations into distinct clonal populations, we identified codominant clones in the majority of patients. Evaluation of intraclonal mutation patterns identified clone-specific punctuated cytosine mutagenesis events, showed that most structural variants are acquired before SNVs, determined that KRAS mutations occur late in disease development but are not sufficient for clonal dominance, and identified clones within the same patient that are arrested at varied stages in B-cell development. Taken together, these data order the sequence of genetic events that underlie childhood ALL and provide a framework for understanding the development of the disease at single-cell resolution.
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