Cell
Volume 173, Issue 4, 3 May 2018, Pages 879-893.e13
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Article
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing

https://doi.org/10.1016/j.cell.2018.03.041Get rights and content
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Highlights

  • Single-cell sequencing of breast cancer patients treated with chemotherapy

  • Patients showed clonal persistence or extinction in response to therapy

  • Resistance occurred through adaptive selection of pre-existing genomic aberrations

  • Chemotherapy induced transcriptional reprogramming of resistant signatures

Summary

Triple-negative breast cancer (TNBC) is an aggressive subtype that frequently develops resistance to chemotherapy. An unresolved question is whether resistance is caused by the selection of rare pre-existing clones or alternatively through the acquisition of new genomic aberrations. To investigate this question, we applied single-cell DNA and RNA sequencing in addition to bulk exome sequencing to profile longitudinal samples from 20 TNBC patients during neoadjuvant chemotherapy (NAC). Deep-exome sequencing identified 10 patients in which NAC led to clonal extinction and 10 patients in which clones persisted after treatment. In 8 patients, we performed a more detailed study using single-cell DNA sequencing to analyze 900 cells and single-cell RNA sequencing to analyze 6,862 cells. Our data showed that resistant genotypes were pre-existing and adaptively selected by NAC, while transcriptional profiles were acquired by reprogramming in response to chemotherapy in TNBC patients.

Keywords

single-cell sequencing
therapy resistance
tumor evolution
triple-negative breast cancer
chemotherapy
breast cancer genomics
intratumor heterogeneity
copy-number evolution
cancer aneuploidy

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These authors contributed equally

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