Whole-genome single-cell copy number profiling from formalin-fixed paraffin-embedded samples

Luciano Martelotto, Timour Baslan, Jude Kendall, Felipe C. Geyer, Kathleen A. Burke, Lee Spraggon, Salvatore Piscuoglio, Kalyani Chadalavada, Gouri Nanjangud, Charlotte K Y Ng, Pamela Moody, Sean D'Italia, Linda Rodgers, Hilary Cox, Arnaud Da Cruz Paula, Asya Stepansky, Michail Schizas, Hannah Y. Wen, Tari A. King, Larry NortonBritta Weigelt, James B. Hicks, Jorge S. Reis-Filho

Research output: Contribution to journalArticleResearchpeer-review

51 Citations (Scopus)


A substantial proportion of tumors consist of genotypically distinct subpopulations of cancer cells. This intratumor genetic heterogeneity poses a substantial challenge for the implementation of precision medicine. Single-cell genomics constitutes a powerful approach to resolve complex mixtures of cancer cells by tracing cell lineages and discovering cryptic genetic variations that would otherwise be obscured in tumor bulk analyses. Because of the chemical alterations that result from formalin fixation, single-cell genomic approaches have largely remained limited to fresh or rapidly frozen specimens. Here we describe the development and validation of a robust and accurate methodology to perform whole-genome copy-number profiling of single nuclei obtained from formalin-fixed paraffin-embedded clinical tumor samples. We applied the single-cell sequencing approach described here to study the progression from in situ to invasive breast cancer, which revealed that ductal carcinomas in situ show intratumor genetic heterogeneity at diagnosis and that these lesions may progress to invasive breast cancer through a variety of evolutionary processes.

Original languageEnglish
Pages (from-to)376-385
Number of pages10
JournalNature Medicine
Issue number3
Publication statusPublished - 1 Mar 2017
Externally publishedYes

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