Research Papers:

A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer

Runze Jiang _, Yi-Tsung Lu, Hao Ho, Bo Li, Jie-Fu Chen, Millicent Lin, Fuqiang Li, Kui Wu, Hanjie Wu, Jake Lichterman, Haolei Wan, Chia-Lun Lu, William OuYang, Ming Ni, Linlin Wang, Guibo Li, Tom Lee, Xiuqing Zhang, Jonathan Yang, Matthew Rettig, Leland W.K. Chung, Huanming Yang, Ker-Chau Li, Yong Hou, Hsian-Rong Tseng, Shuang Hou, Xun Xu, Jun Wang and Edwin M. Posadas

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Oncotarget. 2015; 6:44781-44793. https://doi.org/10.18632/oncotarget.6330

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Runze Jiang1,, Yi-Tsung Lu2,, Hao Ho3,4,, Bo Li1,, Jie-Fu Chen2,5, Millicent Lin5, Fuqiang Li1, Kui Wu1, Hanjie Wu1, Jake Lichterman2, Haolei Wan6, Chia-Lun Lu2, William OuYang5, Ming Ni1, Linlin Wang1, Guibo Li1, Tom Lee7, Xiuqing Zhang8, Jonathan Yang5, Matthew Rettig9,10, Leland W.K. Chung2,*, Huanming Yang1,11,12,*, Ker-Chau Li3,4,*, Yong Hou1,*, Hsian-Rong Tseng5,7,*, Shuang Hou5,*, Xun Xu1,*, Jun Wang1,11,13,*, Edwin M. Posadas2,*

1Beijing Genome Institute-Shenzhen, Shenzhen 51803, China

2Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA

3Department of Statistics, University of California, Los Angeles, CA 90095, USA

4Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan

5Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA

6Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA

7California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA

8The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 51803, China

9Departments of Medicine and Urology, University of California, Los Angeles, CA 90095, USA

10Department of Medicine, Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA

11Princess Al Jawhara Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia

12James D. Watson Institute of Genome Sciences, Zhejiang University, Hangzhou 310058, China

13Department of Biology and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 1599, Denmark

These authors have contributed equally to this work

*Jointed corresponding authors

Correspondence to:

Edwin M. Posadas, e-mail: [email protected]

Jun Wang, e-mail: [email protected]

Hsian-Rong Tseng, e-mail: [email protected]

Keywords: circulating tumor cell, prostate cancer, whole genome sequencing, liquid biopsy, cancer heterogeneity

Received: August 05, 2015     Accepted: October 23, 2015     Published: November 05, 2015


Previous studies have demonstrated focal but limited molecular similarities between circulating tumor cells (CTCs) and biopsies using isolated genetic assays. We hypothesized that molecular similarity between CTCs and tissue exists at the single cell level when characterized by whole genome sequencing (WGS). By combining the NanoVelcro CTC Chip with laser capture microdissection (LCM), we developed a platform for single-CTC WGS. We performed this procedure on CTCs and tissue samples from a patient with advanced prostate cancer who had serial biopsies over the course of his clinical history. We achieved 30X depth and ≥ 95% coverage. Twenty-nine percent of the somatic single nucleotide variations (SSNVs) identified were founder mutations that were also identified in CTCs. In addition, 86% of the clonal mutations identified in CTCs could be traced back to either the primary or metastatic tumors. In this patient, we identified structural variations (SVs) including an intrachromosomal rearrangement in chr3 and an interchromosomal rearrangement between chr13 and chr15. These rearrangements were shared between tumor tissues and CTCs. At the same time, highly heterogeneous short structural variants were discovered in PTEN, RB1, and BRCA2 in all tumor and CTC samples. Using high-quality WGS on single-CTCs, we identified the shared genomic alterations between CTCs and tumor tissues. This approach yielded insight into the heterogeneity of the mutational landscape of SSNVs and SVs. It may be possible to use this approach to study heterogeneity and characterize the biological evolution of a cancer during the course of its natural history.

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