Journal
CELL
Volume 173, Issue 4, Pages 879-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2018.03.041
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Funding
- Lefkofsky Family Foundation
- NCI [1RO1CA169244-01]
- American Cancer Society [129098-RSG-16-092-01-TBG]
- MD Anderson Sequencing Core Facility Grant [CA016672]
- Flow Cytometry Facility grant from the NIH [CA016672]
- Breast Cancer Research Foundation [N013869]
- Swedish Cancer Society [CAN 2015/713]
- Cancer Society in Stockholm [154132, 081141]
- KI-MDACC grant from the Sister Network Institution Fund and GAP program at MD Anderson [40033]
- StratCan at the Karolinska Institute
- ALA Fellowship
- Susan Komen Postdoctoral Fellowship [PDF17487910]
- AACR Basic Cancer Research Fellowship [17-40-42-GAO]
- Roche
- Swedish Breast Cancer Association
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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 preexisting 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.
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