title: A comparison of isolated circulating tumor cells and tissue biopsies using whole-genome sequencing in prostate cancer.
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.
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Runze
authors.initials: R
authors.lastname: Jiang
authors.affiliation: Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Yi-Tsung
authors.initials: YT
authors.lastname: Lu
authors.affiliation: Department of Statistics, University of California, Los Angeles, CA 90095, USA.|Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Hao
authors.initials: H
authors.lastname: Ho
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Jie-Fu
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Millicent
authors.initials: M
authors.lastname: Lin
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Fuqiang
authors.initials: F
authors.lastname: Li
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Wu
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Hanjie
authors.initials: H
authors.lastname: Wu
authors.affiliation: Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Lichterman
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Haolei
authors.initials: H
authors.lastname: Wan
authors.affiliation: Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Chia-Lun
authors.initials: CL
authors.lastname: Lu
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: William
authors.initials: W
authors.lastname: OuYang
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Ni
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Guibo
authors.initials: G
authors.lastname: Li
authors.affiliation: California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Tom
authors.initials: T
authors.lastname: Lee
authors.affiliation: The Guangdong Enterprise Key Laboratory of Human Disease Genomics, BGI-Shenzhen, Shenzhen 51803, China.
authors.forename: Xiuqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Departments of Medicine and Urology, University of California, Los Angeles, CA 90095, USA.|Department of Medicine, Division of Hematology-Oncology, VA Greater Los Angeles Healthcare System, Los Angeles, CA 90073, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Rettig
authors.affiliation: Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Leland W K
authors.initials: LW
authors.lastname: Chung
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.|Princess Al Jawhara Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.|James D. Watson Institute of Genome Sciences, Zhejiang University, Hangzhou 310058, China.
authors.forename: Huanming
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Statistics, University of California, Los Angeles, CA 90095, USA.|Institute of Statistical Sciences, Academia Sinica, Taipei 11529, Taiwan.
authors.forename: Ker-Chau
authors.initials: KC
authors.lastname: Li
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Hou
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.|California NanoSystems Institute, University of California, Los Angeles, CA 90095, USA.
authors.forename: Hsian-Rong
authors.initials: HR
authors.lastname: Tseng
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095, USA.
authors.forename: Shuang
authors.initials: S
authors.lastname: Hou
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Xu
authors.affiliation: Beijing Genome Institute-Shenzhen, Shenzhen 51803, China.|Princess Al Jawhara Centre of Excellence in Research of Hereditary Disorders, King Abdulaziz University, Jeddah 21589, Saudi Arabia.|Department of Biology and the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen 1599, Denmark.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Urologic Oncology Research Program, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Edwin M
authors.initials: EM
authors.lastname: Posadas
mesh_terms: D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D002469:Cell Separation; D002877:Chromosomes, Human; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D023281:Genomics / Q000379:methods*; D006801:Humans; D061346:Laser Capture Microdissection; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D036103:Nanotechnology; D009360:Neoplastic Cells, Circulating / Q000737:chemistry* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011471:Prostatic Neoplasms / Q000097:blood / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor
keywords: cancer heterogeneity; circulating tumor cell; liquid biopsy; prostate cancer; whole genome sequencing