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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):17947-52. doi: 10.1073/pnas.1420822111. Epub 2014 Nov 25.

Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics.

Author information

1
Division of Pediatric Hematology-Oncology, Department of Pediatrics, Stanford University, Palo Alto, CA 94305; and Departments of Bioengineering and Applied Physics, Stanford University and Howard Hughes Medical Institute, Stanford,CA 94305.
2
Departments of Bioengineering and Applied Physics, Stanford University and Howard Hughes Medical Institute, Stanford,CA 94305.
3
Departments of Bioengineering and Applied Physics, Stanford University and Howard Hughes Medical Institute, Stanford,CA 94305 quake@stanford.edu.

Abstract

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.

KEYWORDS:

acute lymphoblastic leukemia; clonal evolution; cytosine mutagenesis; intratumor heterogeneity; single-cell genomics

PMID:
25425670
PMCID:
PMC4273416
DOI:
10.1073/pnas.1420822111
[Indexed for MEDLINE]
Free PMC Article

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