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. Combination of single-cell DNA and RNA sequencing depicts the evolutionary trajectories of chemoresistance in human triple-negative breast cancer at the genomic and transcriptomic level, highlighting the presence of pre-existing genomic alterations and transcriptional reprogramming of resistant signatures.
Original language | English (US) |
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Pages (from-to) | 879-893.e13 |
Journal | Cell |
Volume | 173 |
Issue number | 4 |
DOIs | |
State | Published - May 3 2018 |
Keywords
- breast cancer genomics
- cancer aneuploidy
- chemotherapy
- copy-number evolution
- intratumor heterogeneity
- single-cell sequencing
- therapy resistance
- triple-negative breast cancer
- tumor evolution
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology
MD Anderson CCSG core facilities
- Advanced Technology Genomics Core
- Flow Cytometry and Cellular Imaging Facility