Tumour evolution inferred by single-cell sequencing

Nicholas Navin, Jude Kendall, Jennifer Troge, Peter Andrews, Linda Rodgers, Jeanne McIndoo, Kerry Cook, Asya Stepansky, Dan Levy, Diane Esposito, Lakshmi Muthuswamy, Alex Krasnitz, W. Richard McCombie, James Hicks, Michael Wigler

Research output: Contribution to journalArticlepeer-review

1957 Scopus citations

Abstract

Genomic analysis provides insights into the role of copy number variation in disease, but most methods are not designed to resolve mixed populations of cells. In tumours, where genetic heterogeneity is common, very important information may be lost that would be useful for reconstructing evolutionary history. Here we show that with flow-sorted nuclei, whole genome amplification and next generation sequencing we can accurately quantify genomic copy number within an individual nucleus. We apply single-nucleus sequencing to investigate tumour population structure and evolution in two human breast cancer cases. Analysis of 100 single cells from a polygenomic tumour revealed three distinct clonal subpopulations that probably represent sequential clonal expansions. Additional analysis of 100 single cells from a monogenomic primary tumour and its liver metastasis indicated that a single clonal expansion formed the primary tumour and seeded the metastasis. In both primary tumours, we also identified an unexpectedly abundant subpopulation of genetically diverse pseudodiploidcells that do not travel to the metastatic site. In contrast to gradual models of tumour progression, our data indicate that tumours grow by punctuated clonal expansions with few persistent intermediates.

Original languageEnglish (US)
Pages (from-to)90-95
Number of pages6
JournalNature
Volume472
Issue number7341
DOIs
StatePublished - Apr 7 2011

ASJC Scopus subject areas

  • General

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