Single-cell sequencing deciphers a convergent evolution of copy number alterations from primary to circulating tumor cells

Yan Gao; Xiaohui Ni; Hua Guo; Zhe Su; Yi Ba; Zhongsheng Tong; Zhi Guo; Xin Yao; Xixi Chen; Jian Yin; Zhao Yan; Lin Guo; Ying Liu; Fan Bai; X. Sunney Xie; Ning Zhang

doi:10.1101/gr.216788.116

Single-cell sequencing deciphers a convergent evolution of copy number alterations from primary to circulating tumor cells

¹Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China;
²Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA;
³Department of Cancer Cell Biology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China;
⁴Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China;
⁵Department of Gastrointestinal Oncology,
⁶Department of Breast Oncology,
⁷Department of Interventional Therapy,
⁸Department of Urologic Oncology,
⁹Department of Breast Reconstruction, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China;
¹⁰Pharmacological Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China

↵11 These authors contributed equally to this work.

Corresponding authors: fbai{at}pku.edu.cn, xie{at}chemistry.harvard.edu, zhangning{at}tmu.edu.cn

Abstract

Copy number alteration (CNA) is a major contributor to genome instability, a hallmark of cancer. Here, we studied genomic alterations in single primary tumor cells and circulating tumor cells (CTCs) from the same patient. Single-nucleotide variants (SNVs) in single cells from both samples occurred sporadically, whereas CNAs among primary tumor cells emerged accumulatively rather than abruptly, converging toward the CNA in CTCs. Focal CNAs affecting the MYC gene and the PTEN gene were observed only in a minor portion of primary tumor cells but were present in all CTCs, suggesting a strong selection toward metastasis. Single-cell structural variant (SV) analyses revealed a two-step mechanism, a complex rearrangement followed by gene amplification, for the simultaneous formation of anomalous CNAs in multiple chromosome regions. Integrative CNA analyses of 97 CTCs from 23 patients confirmed the convergence of CNAs and revealed single, concurrent, and mutually exclusive CNAs that could be the driving events in cancer metastasis.

Footnotes

[Supplemental material is available for this article.]
Article published online before print. Article, supplemental material, and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.216788.116.

Received October 4, 2016.
Accepted May 3, 2017.

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