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

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Abstract

// Runze Jiang 1, † , Yi-Tsung Lu 2, † , Hao Ho 3, 4, † , Bo Li 1, † , Jie-Fu Chen 2, 5 , Millicent Lin 5 , Fuqiang Li 1 , Kui Wu 1 , Hanjie Wu 1 , Jake Lichterman 2 , Haolei Wan 6 , Chia-Lun Lu 2 , William OuYang 5 , Ming Ni 1 , Linlin Wang 1 , Guibo Li 1 , Tom Lee 7 , Xiuqing Zhang 8 , Jonathan Yang 5 , Matthew Rettig 9, 10 , Leland W.K. Chung 2, * , Huanming Yang 1, 11, 12, * , Ker-Chau Li 3, 4, * , Yong Hou 1, * , Hsian-Rong Tseng 5, 7, * , Shuang Hou 5, * , Xun Xu 1, * , Jun Wang 1, 11, 13, * , Edwin M. Posadas 2, * 1 Beijing Genome Institute-Shenzhen, Shenzhen 51803, China 2 Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA 3 Department of Statistics, University of California, Los Angeles, CA 90095, USA 4 Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan 5 Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA 6 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA 7 California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA 8 The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 51803, China 9 Departments of Medicine and Urology, University of California, Los Angeles, CA 90095, USA 10 Department of Medicine, Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA 11 Princess Al Jawhara Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia 12 James D. Watson Institute of Genome Sciences, Zhejiang University, Hangzhou 310058, China 13 Department 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: Edwin.Posadas@csmc.edu Jun Wang, e-mail: wangj@genomics.cn Hsian-Rong Tseng, e-mail: HRTseng@mednet.ucla.edu 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 ABSTRACT 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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