Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing
- PMID: 29681456
- PMCID: PMC6132060
- DOI: 10.1016/j.cell.2018.03.041
Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing
Abstract
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: breast cancer genomics; cancer aneuploidy; chemotherapy; copy-number evolution; intratumor heterogeneity; single-cell sequencing; therapy resistance; triple-negative breast cancer; tumor evolution.
Copyright © 2018 Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of Interests
Thomas Hatschek received an institutional grant to Karolinska University Hospital from Roche to support the PROMIX trial.
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Comment in
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Genetic and Phenotypic Diversification of Heterogeneous Tumor Populations.Trends Mol Med. 2018 Aug;24(8):655-656. doi: 10.1016/j.molmed.2018.06.003. Epub 2018 Jun 28. Trends Mol Med. 2018. PMID: 30060834
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