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

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.

Oncotarget. 2015 Nov 05 [Epub ahead of print]

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, Edwin M Posadas

Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. , Department of Statistics, University of California, Los Angeles, CA 90095, USA. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. , Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. , Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. , Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA. , California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA. , Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan. , The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 51803, China. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Department of Statistics, University of California, Los Angeles, CA 90095, USA. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA. , Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Beijing Genome Institute-Shenzhen, Shenzhen 51803, China. , Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.

PubMed