Single-Cell mutational profiling and clonal phylogeny in cancer

Nicola E. Potter, Luca Ermini, Elli Papaemmanuil, Giovanni Cazzaniga, Gowri Vijayaraghavan, Ian Titley, Anthony Ford, Peter Campbell, Lyndal Kearney, Mel Greaves*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

96 Citations (Scopus)


The development of cancer is a dynamic evolutionary process in which intraclonal, genetic diversity provides a substrate for clonal selection and a source of therapeutic escape. The complexity and topography of intraclonal genetic architectures have major implications for biopsy-based prognosis and for targeted therapy. High-depth, next-generation sequencing (NGS) efficiently captures the mutational load of individual tumors or biopsies. But, being a snapshot portrait of total DNA, it disguises the fundamental features of subclonal variegation of genetic lesions and of clonal phylogeny. Single-cell genetic profiling provides a potential resolution to this problem, but methods developed to date all have limitations. We present a novel solution to this challenge using leukemic cells with known mutational spectra as a tractable model. DNA from flow-sorted single cells is screened using multiplex targeted Q-PCR within a microfluidic platform allowing unbiased single-cell selection, high-throughput, and comprehensive analysis for all main varieties of genetic abnormalities: chimeric gene fusions, copy number alterations, and single-nucleotide variants. We show, in this proof-ofprinciple study, that the method has a low error rate and can provide detailed subclonal genetic architectures and phylogenies.

Original languageEnglish
Pages (from-to)2115-2125
Number of pages11
JournalGenome Research
Issue number12
Publication statusPublished - Dec 2013
Externally publishedYes


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