Journal
CLINICAL CANCER RESEARCH
Volume 25, Issue 16, Pages 5049-5060Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-18-3571
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Funding
- National Key Research and Development Program [2016YFC0900102]
- National High Technology Research and Development Program of China (863 Program) [2015AA020403]
- Beijing Natural Science Foundation [7172045]
- Beijing Municipal Science & Technology Commission [Z141100000214013]
- National Natural Sciences Foundation Key Program [81630071, 81330062]
- Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences [CIFMS 2016-I2M-3-008, 2017-I2M-1-005]
- Aiyou Foundation [KY201701]
- Ministry of Education Innovation Team Development Project [IRT-17R10]
- CAMS Key lab of translational research on lung cancer [2018PT31035]
- China National Natural Sciences Foundation [81871889]
- Beijing Novel Program for cross-cooperation [Z181100006218130]
- Non-Profit Central Research Institute Fund of CAMS [2018RC320009]
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Purpose: Genomic analyses of small-cell lung cancer (SCLC) are limited by the availability of tumor specimens. This study aimed to investigate the suitability of single-cell sequencing of circulating tumor cells (CTC) as a method of inferring the evolution and progression of SCLCs. Experimental Design: Between July 1, 2011, and July 28, 2014, 48 consecutively diagnosed patients with SCLC were recruited for this study. CTCs were captured from each patient with CellSearch system. Somatic mutations and copy number alterations (CNA) were monitored by single-cell sequencing of CTCs during chemotherapy. Results: Single-cell sequencing of CTCs can provide a mutational atlas for SCLC. A 10-CNA score based on single CTCs was established as a classifier for outcomes of initial chemotherapy in patients with SCLC. The survival analyses demon-strated that patients with low CNA scores (<0) had significantly prolonged progression-free survival (PFS) and overall survival (OS) after first-line chemotherapy in comparison with those with high scores (>= 0; PFS: 212 days vs. 110.5 days, P = 0.0042; and OS: 223.5 days vs. 424 days, P = 0.0006). The positive predictive value and negative predictive value of the CNA score for clinical subtype (refractory vs. sensitive) were 80.0% and 93.7%, respectively. By tracing allele-specific CNAs in CTCs isolated at different time points during chemotherapy, we showed that CNA heterogeneity might result from allelic losses of initially consistent CNAs. Conclusions: Single CTC-based sequencing can be utilized to depict the genomic profiles and evolutionary history of SCLC, thus offering the potential for clinical stratification of patients with SCLC.
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