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Cell. 2018 May 3;173(4):879-893.e13. doi: 10.1016/j.cell.2018.03.041. Epub 2018 Apr 19.

Chemoresistance Evolution in Triple-Negative Breast Cancer Delineated by Single-Cell Sequencing.

Author information

1
Department of Genetics, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biological Sciences, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
2
Department of Genetics, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
3
Department of Oncology-Pathology, Karolinska Institute, SE-17176 Stockholm, Sweden.
4
Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE-17177 Stockholm, Sweden.
5
Department of Oncology-Pathology, Karolinska Institute, SE-17176 Stockholm, Sweden. Electronic address: theodoros.foukakis@ki.se.
6
Department of Genetics, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biological Sciences, UT MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Bioinformatics and Computational Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: nnavin@mdanderson.org.

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

PMID:
29681456
PMCID:
PMC6132060
DOI:
10.1016/j.cell.2018.03.041
[Indexed for MEDLINE]
Free PMC Article

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