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Siegmund B. Distal Fecal Wash: Intestinal Liquid Biopsy? Cell Mol Gastroenterol Hepatol 2023:S2352-345X(23)00052-8. [PMID: 37130565 DOI: 10.1016/j.jcmgh.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/06/2023] [Accepted: 04/11/2023] [Indexed: 05/04/2023]
Affiliation(s)
- Britta Siegmund
- Division of Gastroenterology, Infectiology and Rheumatology, Charité-Universitätsmedizin Berlin, Corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
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Lin J, Lin W, Bai Y, Liao Y, Lin Q, Chen L, Wu Y. Identification of exosomal hsa-miR-483-5p as a potential biomarker for hepatocellular carcinoma via microRNA expression profiling of tumor-derived exosomes. Exp Cell Res 2022; 417:113232. [PMID: 35659970 DOI: 10.1016/j.yexcr.2022.113232] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/25/2022] [Accepted: 05/28/2022] [Indexed: 11/04/2022]
Abstract
To date, most studies of exosomes related to hepatocellular carcinoma (HCC) have used commercial cancer cell lines or patient plasma as source material. In this study, we isolated exosomes directly from HCC tissues to investigate the potential of exosomal contents as biomarkers for HCC. Exosomes were identified and verified using transmission electron microscopy, nano-flow cytometry analysis, and western blotting. Tissue-derived exosomal miRNA expression was profiled by high-throughput sequencing, and differential expression of miRNAs was validated by quantitative real-time polymerase chain reaction analysis. The diagnostic performance of differentially expressed exosomal miRNAs for HCC was evaluated by receiver operating characteristic curve analysis. Target genes of these miRNAs were verified using luciferase reporter assays, and their functions were studied through in vitro and rescue assays. In total, 225 differentially expressed exosomal miRNAs were identified in HCC samples compared with adjacent liver tissues, and some were associated with HCC tumorigenesis and progression. Comparison of the expression profiles of tissue-derived and plasma-derived exosomal miRNAs identified hsa-miR-483-5p as the only differentially expressed miRNA detected in both HCC tissue and plasma, and this was in a validation group of HCC patients. Analysis of the diagnostic performance of plasma exosomal hsa-miR-483-5p or plasma hsa-miR-483-5p found that both could differentiate HCC and non-HCC cases. In vitro ectopic miR-483-5p expression promoted HCC cell proliferation. CDK15 was confirmed to bind with miR-483-5p directly, and thus, miR-483-5p may function by downregulating CDK15. Hsa-miR-483-5p represents a potential specific and sensitive biomarker for HCC diagnosis.
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Affiliation(s)
- Jie Lin
- Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Wansong Lin
- Laboratory of Immuno-Oncology, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China.
| | - Yannan Bai
- Department of Hepatobiliopancreatic Surgery, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Yanling Liao
- Department of Anesthesiology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Qiaoyan Lin
- Department of Blood Transfusion, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, 350014, Fujian, China
| | - Lingfeng Chen
- Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China
| | - Yijuan Wu
- Department of Pathology, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, Fujian, China
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3
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Mohanty A, Mohanty SK, Rout S, Pani C. Liquid Biopsy, the hype vs. hope in molecular and clinical oncology. Semin Oncol 2021; 48:259-267. [PMID: 34384614 DOI: 10.1053/j.seminoncol.2021.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 05/28/2021] [Accepted: 06/28/2021] [Indexed: 12/12/2022]
Abstract
The molecular landscape of tumors has been traditionally established using a biopsy or resection specimens. These modalities result in sampling bias that offer only a single snapshot of tumor heterogeneity. Over the last decade intensive research towards alleviating such a bias and obtaining an integral yet accurate portrait of the tumors, evolved to the use of established molecular and genetic analysis using blood and several other body fluids, such as urine, saliva, and pleural effusions as liquid biopsies. Genomic profiling of the circulating markers including circulating cell-free tumor DNA (ctDNA), circulating tumor cells (CTCs) or even RNA, proteins, and lipids constituting exosomes, have facilitated the diligent monitoring of response to treatment, allowed one to follow the emergence of drug resistance, and enumerate minimal residual disease. The prevalence of tumor educated platelets (TEPs) and our understanding of how tumor cells influence platelets are beginning to unearth TEPs as a potentially dynamic component of liquid biopsies. Here, we review the biology, methodology, approaches, and clinical applications of biomarkers used to assess liquid biopsies. The current review addresses recent technological advances and different forms of liquid biopsy along with upcoming challenges and how they can be integrated to get the best possible tumor-derived genetic information that can be leveraged to more precise therapies for patient as liquid biopsies become increasingly routine in clinical practice.
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Affiliation(s)
- Abhishek Mohanty
- Rajiv Gandhi Cancer Institute and Research Centre, New Delhi, India.
| | - Sambit K Mohanty
- Advanced Medical Research Institute, Bhubaneswar, Odisha, India; CORE Diagnostics, Gurgaon, Haryana, India
| | - Sipra Rout
- Christian Medical College, Vellore, Tamil Nadu, India
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Plasma Cell-Free Human Papillomavirus Oncogene E6 and E7 DNA Predicts Outcome in Oropharyngeal Squamous Cell Carcinoma. J Mol Diagn 2020; 22:1333-1343. [PMID: 32822851 DOI: 10.1016/j.jmoldx.2020.08.002] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 12/24/2022] Open
Abstract
Persistent human papillomavirus (HPV) infection is associated with the development of oropharyngeal squamous cell carcinoma (OPSCC), and increasing incidences of OPSCC are reported. The generally favorable treatment outcome in patients with HPV-driven OPSCC has brought de-escalation of treatment into discussion. Nevertheless, 13% to 25% develop a relapse within two years after current standard treatment. New biomarkers are urgently required to monitor therapy response, tumor burden, and minimal residual disease during follow-up. This observational study examined 50 patients with OPSCC to investigate plasma cell-free (cf) HPV-DNA derived from tumor cells before therapy and during follow-up. Real-time PCR was applied to quantify the DNA concentration of HPV oncogenes E6 and E7. A total of 85.7% of pretreatment samples from patients with HPV-driven OPSCC (n = 28) were positive for at least one marker, and cfHPV-DNA concentration increased with tumor size. Virtually no signals were detected in HPV-negative OPSCC patients (n = 20; P ≤ 0.001). Patients without clinical evidence of recurrence had significantly reduced cfHPV-DNA concentrations after therapy (P ≤ 0.001). Conversely, cfHPV-DNA levels increased or remained above threshold in five patients who had residual disease or developed recurrence. In conclusion, plasma cfHPV-DNA detection correlates with the clinical course of disease in patients with HPV-driven OPSCC. Consequently, extensive clinical investigation should be considered if cfHPV-DNA is detected during follow-up of patients with HPV-driven OPSCC.
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Court CM, Hou S, Liu L, Winograd P, DiPardo BJ, Liu SX, Chen PJ, Zhu Y, Smalley M, Zhang R, Sadeghi S, Finn RS, Kaldas FM, Busuttil RW, Zhou XJ, Tseng HR, Tomlinson JS, Graeber TG, Agopian VG. Somatic copy number profiling from hepatocellular carcinoma circulating tumor cells. NPJ Precis Oncol 2020; 4:16. [PMID: 32637655 PMCID: PMC7331695 DOI: 10.1038/s41698-020-0123-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Accepted: 05/07/2020] [Indexed: 12/12/2022] Open
Abstract
Somatic copy number alterations (SCNAs) are important genetic drivers of many cancers. We investigated the feasibility of obtaining SCNA profiles from circulating tumor cells (CTCs) as a molecular liquid biopsy for hepatocellular carcinoma (HCC). CTCs from ten HCC patients underwent SCNA profiling. The Cancer Genome Atlas (TCGA) SCNA data were used to develop a cancer origin classification model, which was then evaluated for classifying 44 CTCs from multiple cancer types. Sequencing of 18 CTC samples (median: 4 CTCs/sample) from 10 HCC patients using a low-resolution whole-genome sequencing strategy (median: 0.88 million reads/sample) revealed frequent SCNAs in previously reported HCC regions such as 8q amplifications and 17p deletions. SCNA profiling revealed that CTCs share a median of 80% concordance with the primary tumor. CTCs had SCNAs not seen in the primary tumor, some with prognostic implications. Using a SCNA profiling model, the tissue of origin was correctly identified for 32/44 (73%) CTCs from 12/16 (75%) patients with different cancer types.
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Affiliation(s)
- Colin M. Court
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- Department of Surgery, Veteran’s Health Administration, Greater Los Angeles, Los Angeles, CA USA
- Department of Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, Los Angeles, CA USA
| | - Shuang Hou
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
| | - Lian Liu
- PacGenomics, llc, Los Angeles, CA USA
| | - Paul Winograd
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- Department of Surgery, Veteran’s Health Administration, Greater Los Angeles, Los Angeles, CA USA
| | - Benjamin J. DiPardo
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- Department of Surgery, Veteran’s Health Administration, Greater Los Angeles, Los Angeles, CA USA
| | - Sean X. Liu
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
| | - Pin-Jung Chen
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
| | - Yazhen Zhu
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
| | - Matthew Smalley
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
| | - Ryan Zhang
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
| | - Saeed Sadeghi
- Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA USA
| | - Richard S. Finn
- Department of Medicine, Division of Hematology/Oncology, University of California, Los Angeles, Los Angeles, CA USA
| | - Fady M. Kaldas
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
| | - Ronald W. Busuttil
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA USA
| | - Xianghong J. Zhou
- Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA USA
| | - Hsian-Rong Tseng
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA USA
| | - James S. Tomlinson
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- Department of Surgery, Veteran’s Health Administration, Greater Los Angeles, Los Angeles, CA USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA USA
| | - Thomas G. Graeber
- Department of Molecular, Cellular, and Integrative Physiology, University of California, Los Angeles, Los Angeles, CA USA
- Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA USA
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA USA
| | - Vatche G. Agopian
- Department of Surgery, University of California, Los Angeles, Los Angeles, CA USA
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA USA
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6
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Chen L, Chen Y, Feng YL, Zhu Y, Wang LQ, Hu S, Cheng P. Tumor circulome in the liquid biopsies for digestive tract cancer diagnosis and prognosis. World J Clin Cases 2020; 8:2066-2080. [PMID: 32548136 PMCID: PMC7281040 DOI: 10.12998/wjcc.v8.i11.2066] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 04/10/2020] [Accepted: 04/28/2020] [Indexed: 02/05/2023] Open
Abstract
Digestive tract cancer is one of the main diseases that endanger human health. At present, the early diagnosis of digestive tract tumors mainly depends on serology, imaging, endoscopy, and so on. Although tissue specimens are the gold standard for cancer diagnosis, with the rapid development of precision medicine in cancer, the demand for dynamic monitoring of tumor molecular characteristics has increased. Liquid biopsy involves the collection of body fluids via non-invasive approaches, and analyzes biological markers such as circulating tumor cells, circulating tumor DNA, circulating cell-free DNA, microRNAs, and exosomes. In recent years, liquid biopsy has become more and more important in the diagnosis and prognosis of cancer in clinical practice due to its convenience, non-invasiveness, high specificity and it overcomes temporal-spatial heterogeneity. Therefore, this review summarizes the current evidence on liquid biopsies in digestive tract cancers in relation to diagnosis and prognosis.
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Affiliation(s)
- Long Chen
- Department of Radiotherapy, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Yu Chen
- Department of Pediatric Surgery, Guangdong Women and Children Hospital, Guangzhou 511400, Guangdong Province, China
| | - Yuan-Ling Feng
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Yan Zhu
- Department of Respiratory, Shulan Hospital, Hangzhou 310004, Zhejiang Province, China
| | - Li-Quan Wang
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Shen Hu
- Department of Obstetrics, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
| | - Pu Cheng
- Department of Gynecology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310052, Zhejiang Province, China
- Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Hangzhou 310052, Zhejiang Province, China
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7
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Serrano C, Vivancos A, López-Pousa A, Matito J, Mancuso FM, Valverde C, Quiroga S, Landolfi S, Castro S, Dopazo C, Sebio A, Virgili AC, Menso MM, Martín-Broto J, Sansó M, García-Valverde A, Rosell J, Fletcher JA, George S, Carles J, Arribas J. Clinical value of next generation sequencing of plasma cell-free DNA in gastrointestinal stromal tumors. BMC Cancer 2020; 20:99. [PMID: 32024476 PMCID: PMC7003348 DOI: 10.1186/s12885-020-6597-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 01/31/2020] [Indexed: 02/08/2023] Open
Abstract
Background Gastrointestinal stromal tumor (GIST) initiation and evolution is commonly framed by KIT/PDGFRA oncogenic activation, and in later stages by the polyclonal expansion of resistant subpopulations harboring KIT secondary mutations after the onset of imatinib resistance. Thus, circulating tumor (ct)DNA determination is expected to be an informative non-invasive dynamic biomarker in GIST patients. Methods We performed amplicon-based next-generation sequencing (NGS) across 60 clinically relevant genes in 37 plasma samples from 18 GIST patients collected prospectively. ctDNA alterations were compared with NGS of matched tumor tissue samples (obtained either simultaneously or at the time of diagnosis) and cross-validated with droplet digital PCR (ddPCR). Results We were able to identify cfDNA mutations in five out of 18 patients had detectable in at least one timepoint. Overall, NGS sensitivity for detection of cell-free (cf)DNA mutations in plasma was 28.6%, showing high concordance with ddPCR confirmation. We found that GIST had relatively low ctDNA shedding, and mutations were at low allele frequencies. ctDNA was detected only in GIST patients with advanced disease after imatinib failure, predicting tumor dynamics in serial monitoring. KIT secondary mutations were the only mechanism of resistance found across 10 imatinib-resistant GIST patients progressing to sunitinib or regorafenib. Conclusions ctDNA evaluation with amplicon-based NGS detects KIT primary and secondary mutations in metastatic GIST patients, particularly after imatinib progression. GIST exhibits low ctDNA shedding, but ctDNA monitoring, when positive, reflects tumor dynamics.
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Affiliation(s)
- César Serrano
- Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain. .,Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
| | - Ana Vivancos
- Cancer Genomics Group,
- Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain.
| | | | - Judit Matito
- Cancer Genomics Group,
- Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain
| | - Francesco M Mancuso
- Cancer Genomics Group,
- Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain
| | - Claudia Valverde
- Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain
| | - Sergi Quiroga
- Radiology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Stefania Landolfi
- Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Sandra Castro
- Surgical Oncology Division, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Cristina Dopazo
- Surgical Oncology Division, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Ana Sebio
- Medical Oncology, Sant Pau University Hospital, Barcelona, Spain
| | - Anna C Virgili
- Medical Oncology, Sant Pau University Hospital, Barcelona, Spain
| | - María M Menso
- Radiology Department, Sant Pau University Hospital, Barcelona, Spain
| | | | - Miriam Sansó
- Cancer Genomics Group,
- Vall d'Hebron Institute of Oncology, Natzaret 115, 08035, Barcelona, Spain
| | | | - Jordi Rosell
- Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain
| | - Jonathan A Fletcher
- Pathology Department, Brigham and Women's Hospital/Harvard Medical School, Boston, USA
| | - Suzanne George
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, USA
| | - Joan Carles
- Medical Oncology Department, Vall d'Hebron University Hospital, P. Vall d'Hebron 119, 08035, Barcelona, Spain
| | - Joaquín Arribas
- Preclinical Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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9
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Torga G, Pienta KJ. Patient-Paired Sample Congruence Between 2 Commercial Liquid Biopsy Tests. JAMA Oncol 2019; 4:868-870. [PMID: 29242909 DOI: 10.1001/jamaoncol.2017.4027] [Citation(s) in RCA: 146] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Gonzalo Torga
- The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kenneth J Pienta
- The James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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10
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Iliescu FS, Poenar DP, Yu F, Ni M, Chan KH, Cima I, Taylor HK, Cima I, Iliescu C. Recent advances in microfluidic methods in cancer liquid biopsy. BIOMICROFLUIDICS 2019; 13:041503. [PMID: 31431816 PMCID: PMC6697033 DOI: 10.1063/1.5087690] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 06/24/2019] [Indexed: 05/04/2023]
Abstract
Early cancer detection, its monitoring, and therapeutical prediction are highly valuable, though extremely challenging targets in oncology. Significant progress has been made recently, resulting in a group of devices and techniques that are now capable of successfully detecting, interpreting, and monitoring cancer biomarkers in body fluids. Precise information about malignancies can be obtained from liquid biopsies by isolating and analyzing circulating tumor cells (CTCs) or nucleic acids, tumor-derived vesicles or proteins, and metabolites. The current work provides a general overview of the latest on-chip technological developments for cancer liquid biopsy. Current challenges for their translation and their application in various clinical settings are discussed. Microfluidic solutions for each set of biomarkers are compared, and a global overview of the major trends and ongoing research challenges is given. A detailed analysis of the microfluidic isolation of CTCs with recent efforts that aimed at increasing purity and capture efficiency is provided as well. Although CTCs have been the focus of a vast microfluidic research effort as the key element for obtaining relevant information, important clinical insights can also be achieved from alternative biomarkers, such as classical protein biomarkers, exosomes, or circulating-free nucleic acids. Finally, while most work has been devoted to the analysis of blood-based biomarkers, we highlight the less explored potential of urine as an ideal source of molecular cancer biomarkers for point-of-care lab-on-chip devices.
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Affiliation(s)
- Florina S. Iliescu
- School of Applied Science, Republic Polytechnic, Singapore 738964, Singapore
| | - Daniel P. Poenar
- VALENS-Centre for Bio Devices and Signal Analysis, School of EEE, Nanyang Technological University, Singapore 639798, Singapore
| | - Fang Yu
- Singapore Institute of Manufacturing Technology, A*STAR, Singapore 138634, Singapore
| | - Ming Ni
- School of Biological Sciences and Engineering, Yachay Technological University, San Miguel de Urcuquí 100105, Ecuador
| | - Kiat Hwa Chan
- Division of Science, Yale-NUS College, Singapore 138527, Singapore
| | | | - Hayden K. Taylor
- Department of Mechanical Engineering, University of California, Berkeley, California 94720, USA
| | - Igor Cima
- DKFZ-Division of Translational Oncology/Neurooncology, German Cancer Consortium (DKTK), Heidelberg and University Hospital Essen, Essen 45147, Germany
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11
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Schweizer MT, Gulati R, Beightol M, Konnick EQ, Cheng HH, Klemfuss N, Sarkar ND, Yu EY, Montgomery RB, Nelson PS, Pritchard CC. Clinical determinants for successful circulating tumor DNA analysis in prostate cancer. Prostate 2019; 79:701-708. [PMID: 30865311 PMCID: PMC6589085 DOI: 10.1002/pros.23778] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 01/31/2019] [Indexed: 11/08/2022]
Abstract
BACKGROUND Plasma-based cell-free DNA is an attractive biospecimen for assessing somatic mutations due to minimally-invasive real-time sampling. However, next generation sequencing (NGS) of cell-free DNA (cfDNA) may not be appropriate for all patients with advanced prostate cancer (PC). METHODS Blood was obtained from advanced PC patients for plasma-based sequencing. UW-OncoPlex, a ∼2 Mb multi-gene NGS panel performed in the CLIA/CAP environment, was optimized for detecting cfDNA mutations. Tumor tissue and germline samples were sequenced for comparative analyses. Multivariate logistic regression was performed to determine the clinical characteristic associated with the successful detection of somatic cfDNA alterations (ie detection of at least one clearly somatic PC mutation). RESULTS Plasma for cfDNA sequencing was obtained from 93 PC patients along with tumor tissue (N = 67) and germline (N = 93) controls. We included data from 76 patients (72 prostate adenocarcinoma; 4 variant histology PC) in the analysis. Somatic DNA aberrations were detected in 34 cfDNA samples from patients with prostate adenocarcinoma. High PSA level, high tumor volume, and castration-resistance were significantly associated with successful detection of somatic cfDNA alterations. Among samples with somatic mutations detected, the cfDNA assay detected 93/102 (91%) alterations found in tumor tissue, yielding a clustering-corrected sensitivity of 92% (95% confidence interval 88-97%). All germline pathogenic variants present in lymphocyte DNA were also detected in cfDNA (N = 12). Somatic mutations from cfDNA were detected in 30/33 (93%) instances when PSA was >10 ng/mL. CONCLUSIONS Disease burden, including a PSA >10 ng/mL, is strongly associated with detecting somatic mutations from cfDNA specimens.
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Affiliation(s)
- Michael T. Schweizer
- Department of Medicine, University of Washington
- Clinical Research Division, Fred Hutchinson Cancer Research Center
| | - Roman Gulati
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center
| | | | | | - Heather H. Cheng
- Department of Medicine, University of Washington
- Clinical Research Division, Fred Hutchinson Cancer Research Center
| | - Nola Klemfuss
- Division of Human Biology, Fred Hutchinson Cancer Research Center
- Brotman Baty Institute for Precision Medicine
| | - Navonil De Sarkar
- Department of Medicine, University of Washington
- Division of Human Biology, Fred Hutchinson Cancer Research Center
| | - Evan Y. Yu
- Department of Medicine, University of Washington
- Clinical Research Division, Fred Hutchinson Cancer Research Center
| | - R. Bruce Montgomery
- Department of Medicine, University of Washington
- Clinical Research Division, Fred Hutchinson Cancer Research Center
| | - Peter S. Nelson
- Department of Medicine, University of Washington
- Division of Human Biology, Fred Hutchinson Cancer Research Center
| | - Colin C. Pritchard
- Department of Laboratory Medicine, University of Washington
- Brotman Baty Institute for Precision Medicine
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12
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Chen-Yin O, Vu T, Grunwald JT, Toledano M, Zimak J, Toosky M, Shen B, Zell JA, Gratton E, Abram T, Zhao W. An ultrasensitive test for profiling circulating tumor DNA using integrated comprehensive droplet digital detection. LAB ON A CHIP 2019; 19:993-1005. [PMID: 30735225 PMCID: PMC6559803 DOI: 10.1039/c8lc01399c] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Current cancer detection systems lack the required sensitivity to reliably detect minimal residual disease (MRD) and recurrence at the earliest stages when treatment would be most effective. To address this issue, we present a novel liquid biopsy approach that utilizes an integrated comprehensive droplet digital detection (IC3D) digital PCR system which combines microfluidic droplet partitioning, fluorescent multiplex PCR chemistry, and our rapid 3D, large-volume droplet counting technology. The IC3D ddPCR assay can detect cancer-specific, ultra-rare genomic targets due to large sample input and high degree of partitioning. We first demonstrate our droplet digital PCR assay can robustly detect common cancer mutants including KRAS G12D spiked in wild-type genomic background or isolated from patient samples with 100% specificity. We then demonstrate that the IC3D ddPCR system can detect oncogenic KRAS G12D mutant alleles against a background of wild-type genomes at a sensitivity of 0.00125-0.005% with a false positive rate of 0% which is 50 to 1000× more sensitive than existing commercial liquid biopsy ddPCR and qPCR platforms, respectively. In addition, our technology can uniquely enable detection of circulating tumor cells using their genetic markers without a pre-enrichment step, and analysis of total tumor DNA isolated from blood samples, which will increase clinical sensitivity and specificity, and minimize inter-assay variability. Therefore, our technology holds the potential to provide clinicians with a powerful decision-making tool to monitor and treat MRD with unprecedented sensitivity for earlier stage intervention.
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Affiliation(s)
- Ou Chen-Yin
- Velox Biosystems, 5 Mason, Suite 160, Irvine, CA 92618, USA
| | - Tam Vu
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
| | | | - Michael Toledano
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA
| | - Jan Zimak
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA
| | - Melody Toosky
- Velox Biosystems, 5 Mason, Suite 160, Irvine, CA 92618, USA
| | - Byron Shen
- Velox Biosystems, 5 Mason, Suite 160, Irvine, CA 92618, USA
| | - Jason A. Zell
- Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA
- Division of Hematology/Oncology, University of California Irvine Medical Center, Orange, USA
| | - Enrico Gratton
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
- Laboratory for Fluorescence Dynamics, Department of Biomedical Engineering, University of California, Irvine, USA
| | - Tim Abram
- Velox Biosystems, 5 Mason, Suite 160, Irvine, CA 92618, USA
| | - Weian Zhao
- Sue and Bill Gross Stem Cell Research Center, University of California, Irvine, Irvine, CA 92697, USA
- Department of Pharmaceutical Sciences, University of California, Irvine, Irvine, CA 92697, USA
- Chao Family Comprehensive Cancer Center, University of California, Irvine, Irvine, CA 92697, USA
- Edwards Life Sciences Center for Advanced Cardiovascular Technology, University of California, Irvine, Irvine, CA 92697, USA
- Department of Biomedical Engineering, University of California, Irvine, Irvine, CA 92697, USA
- Department of Biological Chemistry, University of California, Irvine, Irvine, CA 92697, USA
- Division of Hematology/Oncology, University of California Irvine Medical Center, Orange, USA
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13
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Robinson JL, Feizi A, Uhlén M, Nielsen J. A Systematic Investigation of the Malignant Functions and Diagnostic Potential of the Cancer Secretome. Cell Rep 2019; 26:2622-2635.e5. [PMID: 30840886 PMCID: PMC6441842 DOI: 10.1016/j.celrep.2019.02.025] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 01/13/2019] [Accepted: 02/07/2019] [Indexed: 12/16/2022] Open
Abstract
The collection of proteins secreted from a cell-the secretome-is of particular interest in cancer pathophysiology due to its diagnostic potential and role in tumorigenesis. However, cancer secretome studies are often limited to one tissue or cancer type or focus on biomarker prediction without exploring the associated functions. We therefore conducted a pan-cancer analysis of secretome gene expression changes to identify candidate diagnostic biomarkers and to investigate the underlying biological function of these changes. Using transcriptomic data spanning 32 cancer types and 30 healthy tissues, we quantified the relative diagnostic potential of secretome proteins for each cancer. Furthermore, we offer a potential mechanism by which cancer cells relieve secretory pathway stress by decreasing the expression of tissue-specific genes, thereby facilitating the secretion of proteins promoting invasion and proliferation. These results provide a more systematic understanding of the cancer secretome, facilitating its use in diagnostics and its targeting for therapeutic development.
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Affiliation(s)
- Jonathan L Robinson
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Wallenberg Centre for Protein Research, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden
| | - Amir Feizi
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Wallenberg Centre for Protein Research, Chalmers University of Technology, Kemivägen 10, Gothenburg, Sweden; Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark.
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Fitts CA, Ji N, Li Y, Tan C. Exploiting Exosomes in Cancer Liquid Biopsies and Drug Delivery. Adv Healthc Mater 2019; 8:e1801268. [PMID: 30663276 DOI: 10.1002/adhm.201801268] [Citation(s) in RCA: 94] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 12/21/2018] [Indexed: 01/08/2023]
Abstract
Exosomes are cell-derived nanovesicles that transfer molecular cargo from donor to recipient cells and mediate intercellular communication. Advancement in elucidating the biological capabilities and functionalities of exosomes has revealed the striking roles of exosomes as conveyors of bioactive molecules across the biological barriers. Tumor-derived exosomes hold great promise to serve as a liquid biopsy tool for cancer diagnosis and prognosis, as large quantities of exosomes are excreted by tumor cells continuously into the circulation, carrying the molecular cargo (DNA, RNA, proteins) reflective of the genetic and signaling alterations in tumor cells. Two inherent characteristics of exosomes offer important opportunities for drug delivery: their superb transcellular permeability and biocompatibility. Exosomes are uniquely capable of encapsulating a variety of payloads and deliver them to the target tissues. This review discusses the potential of tumor-derived exosomes in cancer liquid biopsies as well as the underlying mechanisms. Furthermore, the recent progress of developing exosomes as highly versatile and efficient drug carriers is also summarized.
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Affiliation(s)
- Coy Austin Fitts
- Department of Pharmaceutics and Drug DeliveryUniversity of Mississippi University, MS 38677 USA
| | - Nan Ji
- Department of Pharmaceutics and Drug DeliveryUniversity of Mississippi University, MS 38677 USA
| | - Yusheng Li
- Department of Pharmaceutics and Drug DeliveryUniversity of Mississippi University, MS 38677 USA
| | - Chalet Tan
- Department of Pharmaceutics and Drug DeliveryUniversity of Mississippi University, MS 38677 USA
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15
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Marshall HT, Djamgoz MBA. Immuno-Oncology: Emerging Targets and Combination Therapies. Front Oncol 2018; 8:315. [PMID: 30191140 PMCID: PMC6115503 DOI: 10.3389/fonc.2018.00315] [Citation(s) in RCA: 234] [Impact Index Per Article: 33.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 07/24/2018] [Indexed: 12/20/2022] Open
Abstract
Host immunity recognizes and eliminates most early tumor cells, yet immunological checkpoints, exemplified by CTLA-4, PD-1, and PD-L1, pose a significant obstacle to effective antitumor immune responses. T-lymphocyte co-inhibitory pathways influence intensity, inflammation and duration of antitumor immunity. However, tumors and their immunosuppressive microenvironments exploit them to evade immune destruction. Recent PD-1 checkpoint inhibitors yielded unprecedented efficacies and durable responses across advanced-stage melanoma, showcasing potential to replace conventional radiotherapy regimens. Neverthless, many clinical problems remain in terms of efficacy, patient-to-patient variability, and undesirable outcomes and side effects. In this review, we evaluate recent advances in the immuno-oncology field and discuss ways forward. First, we give an overview of current immunotherapy modalities, involving mainy single agents, including inhibitor monoclonal antibodies (mAbs) targeting T-cell checkpoints of PD-1 and CTLA-4. However, neoantigen recognition alone cannot eliminate tumors effectively in vivo given their inherent complex micro-environment, heterogeneous nature and stemness. Then, based mainly upon CTLA-4 and PD-1 checkpoint inhibitors as a "backbone," we cover a range of emerging ("second-generation") therapies incorporating other immunotherapies or non-immune based strategies in synergistic combination. These include targeted therapies such as tyrosine kinase inhibitors, co-stimulatory mAbs, bifunctional agents, epigenetic modulators (such as inhibitors of histone deacetylases or DNA methyltransferase), vaccines, adoptive-T-cell therapy, nanoparticles, oncolytic viruses, and even synthetic "gene circuits." A number of novel immunotherapy co-targets in pre-clinical development are also introduced. The latter include metabolic components, exosomes and ion channels. We discuss in some detail of the personalization of immunotherapy essential for ultimate maximization of clinical outcomes. Finally, we outline possible future technical and conceptual developments including realistic in vitro and in vivo models and inputs from physics, engineering, and artificial intelligence. We conclude that the breadth and quality of immunotherapeutic approaches and the types of cancers that can be treated will increase significantly in the foreseeable future.
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Affiliation(s)
- Henry T Marshall
- Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, London, United Kingdom
| | - Mustafa B A Djamgoz
- Neuroscience Solutions to Cancer Research Group, Department of Life Sciences, Imperial College London, London, United Kingdom
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16
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Robado de Lope L, Alcíbar OL, Amor López A, Hergueta-Redondo M, Peinado H. Tumour-adipose tissue crosstalk: fuelling tumour metastasis by extracellular vesicles. Philos Trans R Soc Lond B Biol Sci 2018; 373:rstb.2016.0485. [PMID: 29158314 DOI: 10.1098/rstb.2016.0485] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/14/2017] [Indexed: 12/12/2022] Open
Abstract
During metastasis, tumour cells must communicate with their microenvironment by secreted soluble factors and extracellular vesicles. Different stromal cell types (e.g. bone marrow-derived cells, endothelial cells and fibroblasts) influence the growth and progression of tumours. In recent years, interest has extended to other cell types in the tumour microenvironment such as adipocytes and adipose tissue-derived mesenchymal stem cells. Indeed, obesity is becoming pandemic in some developing countries and it is now considered to be a risk factor for cancer progression. However, the true impact of obesity on the metastatic behaviour of tumours is still not yet fully understood. In this 'Perspective' article, we will discuss the potential influence of obesity on tumour metastasis, mainly in melanoma, breast and ovarian cancer. We summarize the main mechanisms involved with special attention to the role of extracellular vesicles in this process. We envisage that besides having a direct impact on tumour cells, obesity systemically preconditions the tumour microenvironment for future metastasis by favouring the formation of pro-inflammatory niches.This article is part of the discussion meeting issue 'Extracellular vesicles and the tumour microenvironment'.
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Affiliation(s)
- Lucía Robado de Lope
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Olwen Leaman Alcíbar
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Ana Amor López
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Marta Hergueta-Redondo
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain
| | - Héctor Peinado
- Microenvironment and Metastasis Group, Department of Molecular Oncology, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain .,Children's Cancer and Blood Foundation Laboratories. Department of Pediatrics, Drukier Institute for Children's Health and Meyer Cancer Center, Belfer Research Building, Weill Cornell Medicine, New York, NY 10021, USA
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17
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Ou SHI, Nagasaka M, Zhu VW. Liquid Biopsy to Identify Actionable Genomic Alterations. Am Soc Clin Oncol Educ Book 2018; 38:978-997. [PMID: 30231331 PMCID: PMC6865813 DOI: 10.1200/edbk_199765] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify "shedders" and "nonshedders" of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.
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Affiliation(s)
- Sai-Hong Ignatius Ou
- From Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Karmanos Cancer Center, Wayne State University, Detroit, MI; Hematology/Oncology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA
| | - Misako Nagasaka
- From Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Karmanos Cancer Center, Wayne State University, Detroit, MI; Hematology/Oncology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA
| | - Viola W Zhu
- From Chao Family Comprehensive Cancer Center, University of California Irvine School of Medicine, Orange, CA; Karmanos Cancer Center, Wayne State University, Detroit, MI; Hematology/Oncology Section, Veterans Affairs Long Beach Healthcare System, Long Beach, CA
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18
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Kumar M, Choudhury Y, Ghosh SK, Mondal R. Application and optimization of minimally invasive cell-free DNA techniques in oncogenomics. Tumour Biol 2018; 40:1010428318760342. [PMID: 29484962 DOI: 10.1177/1010428318760342] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The conventional method of measuring biomarkers in malignant tissue samples has already given subversive growth in cancer diagnosis, prognosis, and therapy selection. However, the regression and heterogeneity associated with tumor tissue biopsy have urged for the development of an alternative approach. Considering the limitations, cell-free DNA has emerged as a surrogate alternative, facilitating preoperative chemoradiotherapy (p < 0.0001) treatment response in rectal cancer and detection of biomarker in lung cancer. This potential of cell-free DNA in several other cancers has yet to be explored based on clinical relevance by optimizing the preanalytical factors. This review has highlighted the crucial parameters from blood collection to cell-free DNA analysis that has a significant impact on the accuracy and reliability of clinical data. The quantity of cell-free DNA is also a limiting factor. Therefore, a proper preanalytical factor for blood collection, its stability, centrifugation speed, and plasma storage condition are to be optimized for developing cancer-specific biomarkers useful for clinical purpose. Liquid biopsy-based origin of cell-free DNA has revolutionized the area of cancer research. Lack of preanalytical and analytical procedures may be considered for identification of novel biomarkers through next-generation sequencing of tumor-originated cell-free DNA in contradiction to tissue biopsy for cancer-specific biomarkers.
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Affiliation(s)
- Manish Kumar
- 1 Department of Biotechnology, Assam University, Silchar, India
| | | | - Sankar Kumar Ghosh
- 1 Department of Biotechnology, Assam University, Silchar, India.,2 University of Kalyani, Kalyani, India
| | - Rosy Mondal
- 3 Life Sciences Division, Institute of Advanced Study in Science and Technology, Guwahati, India
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20
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Sheridan C. Grail to pour $1 billion into blood test to detect early cancer. Nat Biotechnol 2018; 35:101-102. [PMID: 28178244 DOI: 10.1038/nbt0217-101] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
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21
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Genetic profiling of cancer with circulating tumor DNA analysis. J Genet Genomics 2018; 45:79-85. [DOI: 10.1016/j.jgg.2017.11.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 11/24/2017] [Accepted: 11/25/2017] [Indexed: 12/21/2022]
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22
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EV, Microvesicles/MicroRNAs and Stem Cells in Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1056:123-135. [PMID: 29754178 DOI: 10.1007/978-3-319-74470-4_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The role of extracellular vesicles (EV) in carcinogenesis has become the focus of much research. These microscopic messengers have been found to regulate immune system function, particularly in tumorigenesis, as well as conditioning future metastatic sites for the attachment and growth of tumor tissue. Through an interaction with a range of host tissues, EVs are able to generate a pro-tumor environment that is essential for tumorigenesis. These small nanovesicles are an ideal candidate for a non-invasive indicator of pathogenesis and/or disease progression as they can display individualized nucleic acid, protein, and lipid expression profiles that are often reflective of disease state, and can be easily detected in bodily fluids, even after extended cryo-storage. Furthermore, the ability of EVs to securely transport signaling molecules and localize to distant tissues suggests these particles may greatly improve the delivery of therapeutic treatments, particularly in cancer. In this chapter, we discuss the role of EV in the identification of new diagnostic and prognostic cancer biomarkers, as well as the development of novel EV-based cancer therapies.
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23
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Almodovar K, Iams WT, Meador CB, Zhao Z, York S, Horn L, Yan Y, Hernandez J, Chen H, Shyr Y, Lim LP, Raymond CK, Lovly CM. Longitudinal Cell-Free DNA Analysis in Patients with Small Cell Lung Cancer Reveals Dynamic Insights into Treatment Efficacy and Disease Relapse. J Thorac Oncol 2018; 13:112-123. [PMID: 28951314 PMCID: PMC5827950 DOI: 10.1016/j.jtho.2017.09.1951] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2017] [Revised: 08/16/2017] [Accepted: 09/08/2017] [Indexed: 12/23/2022]
Abstract
INTRODUCTION Patients with SCLC have a poor prognosis and limited treatment options. Because access to longitudinal tumor samples is very limited in patients with this disease, we chose to focus our studies on the characterization of plasma cell-free DNA (cfDNA) for rapid, noninvasive monitoring of disease burden. METHODS We developed a liquid biopsy assay that quantifies somatic variants in cfDNA. The assay detects single nucleotide variants, copy number alterations, and insertions or deletions in 14 genes that are frequently mutated in SCLC, including tumor protein p53 gene (TP53), retinoblastoma 1 gene (RB1), BRAF, KIT proto-oncogene receptor tyrosine kinase gene (KIT), notch 1 gene (NOTCH1), notch 2 gene (NOTCH2), notch 3 gene (NOTCH3), notch 4 gene (NOTCH4), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA), phosphatase and tensin homolog gene (PTEN), fibroblast growth factor receptor 1 gene (FGFR1), v-myc avian myelocytomatosis viral oncogene homolog gene (MYC), v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog gene (MYCL1), and v-myc avian myelocytomatosis viral oncogene neuroblastoma derived homolog gene (MYCN). RESULTS Over the course of 26 months of peripheral blood collection, we examined 140 plasma samples from 27 patients. We detected disease-associated mutations in 85% of patient samples with mutant allele frequencies ranging from 0.1% to 87%. In our cohort, 59% of the patients had extensive-stage disease, and the most common mutations occurred in TP53 (70%) and RB1 (52%). In addition to mutations in TP53 and RB1, we detected alterations in 10 additional genes in our patient population (PTEN, NOTCH1, NOTCH2, NOTCH3, NOTCH4, MYC, MYCL1, PIK3CA, KIT, and BRAF). The observed allele frequencies and copy number alterations tracked closely with treatment responses. Notably, in several cases analysis of cfDNA provided evidence of disease relapse before conventional imaging. CONCLUSIONS These results suggest that liquid biopsies are readily applicable in patients with SCLC and can potentially provide improved monitoring of disease burden, depth of response to treatment, and timely warning of disease relapse in patients with this disease.
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Affiliation(s)
- Karinna Almodovar
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Wade T. Iams
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Catherine B. Meador
- Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN
| | - Zhiguo Zhao
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Sally York
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Leora Horn
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Yingjun Yan
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | | | - Heidi Chen
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | - Yu Shyr
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
| | | | | | - Christine M. Lovly
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN,Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN,Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN,Corresponding author: Christine M. Lovly, MD, PhD, Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN 37232-6307, Phone 615-936-3457,
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Bhome R, Goh RW, Bullock MD, Pillar N, Thirdborough SM, Mellone M, Mirnezami R, Galea D, Veselkov K, Gu Q, Underwood TJ, Primrose JN, De Wever O, Shomron N, Sayan AE, Mirnezami AH. Exosomal microRNAs derived from colorectal cancer-associated fibroblasts: role in driving cancer progression. Aging (Albany NY) 2017; 9:2666-2694. [PMID: 29283887 PMCID: PMC5764398 DOI: 10.18632/aging.101355] [Citation(s) in RCA: 118] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Accepted: 12/17/2017] [Indexed: 12/12/2022]
Abstract
Colorectal cancer is a global disease with increasing incidence. Mortality is largely attributed to metastatic spread and therefore, a mechanistic dissection of the signals which influence tumor progression is needed. Cancer stroma plays a critical role in tumor proliferation, invasion and chemoresistance. Here, we sought to identify and characterize exosomal microRNAs as mediators of stromal-tumor signaling. In vitro, we demonstrated that fibroblast exosomes are transferred to colorectal cancer cells, with a resultant increase in cellular microRNA levels, impacting proliferation and chemoresistance. To probe this further, exosomal microRNAs were profiled from paired patient-derived normal and cancer-associated fibroblasts, from an ongoing prospective biomarker study. An exosomal cancer-associated fibroblast signature consisting of microRNAs 329, 181a, 199b, 382, 215 and 21 was identified. Of these, miR-21 had highest abundance and was enriched in exosomes. Orthotopic xenografts established with miR-21-overexpressing fibroblasts and CRC cells led to increased liver metastases compared to those established with control fibroblasts. Our data provide a novel stromal exosome signature in colorectal cancer, which has potential for biomarker validation. Furthermore, we confirmed the importance of stromal miR-21 in colorectal cancer progression using an orthotopic model, and propose that exosomes are a vehicle for miR-21 transfer between stromal fibroblasts and cancer cells.
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Affiliation(s)
- Rahul Bhome
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
- University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Rebecca W. Goh
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Marc D. Bullock
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
- University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Nir Pillar
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Stephen M. Thirdborough
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Massimiliano Mellone
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Reza Mirnezami
- Department of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London SW7 2BB, UK
| | - Dieter Galea
- Department of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London SW7 2BB, UK
| | - Kirill Veselkov
- Department of Surgery and Cancer, Imperial College London, Sir Alexander Fleming Building, London SW7 2BB, UK
| | - Quan Gu
- University of Glasgow Centre for Virus Research, 117 Sir Michael Stoker Building, Glasgow G61 1QH, UK
| | - Timothy J. Underwood
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
- University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - John N. Primrose
- University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Olivier De Wever
- Department of Experimental Cancer Research, Ghent University, Radiotherapiepark, 9000 Ghent, Belgium
| | - Noam Shomron
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - A. Emre Sayan
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
| | - Alex H. Mirnezami
- Cancer Sciences, University of Southampton, Somers Building, Southampton General Hospital, Southampton SO16 6YD, UK
- University Surgical Unit, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK
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25
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García-Casas A, García-Olmo DC, García-Olmo D. Further the liquid biopsy: Gathering pieces of the puzzle of genometastasis theory. World J Clin Oncol 2017; 8:378-388. [PMID: 29067274 PMCID: PMC5638713 DOI: 10.5306/wjco.v8.i5.378] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2017] [Revised: 08/03/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Metastasis is the major cause of mortality in cancer disease and still constitutes one of the most controversial mechanism, not yet fully understood. What is almost beyond doubt is that circulatory system is crucial for cancer propagation. Regarding this system, much attention has been recently paid to liquid biopsy. This technique is aimed to detect circulating tumor cells (CTCs) and circulating nucleic acids so it can be used as a tool for diagnostic, prognostic and follow-up of patients. Whereas CTCs tend to be scarce in serum and plasma from cancer patient, abundant circulating nucleic acids can be detected in the same location. This fact, together with the genetic origin of cancer, stands out the relevance of circulating nucleic acids and shed light into the role of nucleic acids as drivers of metastasis, a recently discovered phenomenon called Genometastasis. This innovative theory supports the transfer of oncogenes from cancer cells to normal and susceptible cells located in distant target organs through circulatory system. What is more, many biological processes haven been described to deliver and secrete circulating nucleic acids into the circulation which can allow such horizontal transfer of oncogenes. In this review, we focus not only on these mechanisms but also we demonstrate its putative role in cancer propagation and give insights about possible therapeutic strategies based on this theory. Our objective is to demonstrate how findings about cell-to-cell communications and previous results can agree with this unprecedented theory.
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Affiliation(s)
| | - Dolores C García-Olmo
- Centre de Recerca Experimental Biomèdica Aplicada(CREBA), IRBLLEIDA, 25138 Lleida, Spain
| | - Damián García-Olmo
- Department of Surgery, Universidad Autónoma de Madrid, Instituto de Investigación Sanitaria, Fundación Jiménez Díaz, 28050 Madrid, Spain
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Han X, Wang J, Sun Y. Circulating Tumor DNA as Biomarkers for Cancer Detection. GENOMICS, PROTEOMICS & BIOINFORMATICS 2017; 15:59-72. [PMID: 28392479 PMCID: PMC5414889 DOI: 10.1016/j.gpb.2016.12.004] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 12/13/2016] [Accepted: 12/20/2016] [Indexed: 12/23/2022]
Abstract
Detection of circulating tumor DNAs (ctDNAs) in cancer patients is an important component of cancer precision medicine ctDNAs. Compared to the traditional physical and biochemical methods, blood-based ctDNA detection offers a non-invasive and easily accessible way for cancer diagnosis, prognostic determination, and guidance for treatment. While studies on this topic are currently underway, clinical translation of ctDNA detection in various types of cancers has been attracting much attention, due to the great potential of ctDNA as blood-based biomarkers for early diagnosis and treatment of cancers. ctDNAs are detected and tracked primarily based on tumor-related genetic and epigenetic alterations. In this article, we reviewed the available studies on ctDNA detection and described the representative methods. We also discussed the current understanding of ctDNAs in cancer patients and their availability as potential biomarkers for clinical purposes. Considering the progress made and challenges involved in accurate detection of specific cell-free nucleic acids, ctDNAs hold promise to serve as biomarkers for cancer patients, and further validation is needed prior to their broad clinical use.
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Affiliation(s)
- Xiao Han
- CAS Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junyun Wang
- CAS Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yingli Sun
- CAS Key Laboratory of Genomic and Precision Medicine, China Gastrointestinal Cancer Research Center, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.
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Wan JCM, Massie C, Garcia-Corbacho J, Mouliere F, Brenton JD, Caldas C, Pacey S, Baird R, Rosenfeld N. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer 2017; 17:223-238. [PMID: 28233803 DOI: 10.1038/nrc.2017.7] [Citation(s) in RCA: 1734] [Impact Index Per Article: 216.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a 'liquid biopsy' for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.
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Affiliation(s)
- Jonathan C M Wan
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
| | - Charles Massie
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
| | - Javier Garcia-Corbacho
- Clinical Trials Unit, Clinic Institute of Haematological and Oncological Diseases, Hospital Clinic de Barcelona, IDIBAPs, Carrer de Villarroel, 170 Barcelona 08036, Spain
| | - Florent Mouliere
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
| | - James D Brenton
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
| | - Carlos Caldas
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
- Department of Oncology, University of Cambridge Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Simon Pacey
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
- Department of Oncology, University of Cambridge Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Richard Baird
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
- Department of Oncology, University of Cambridge Hutchison-MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK
| | - Nitzan Rosenfeld
- Cancer Research UK Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK
- Cancer Research UK Cambridge Centre, Cambridge CB2 0RE, UK
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28
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Erratum: The cancer bloodhounds. Nat Biotechnol 2017; 35:178. [DOI: 10.1038/nbt0217-178c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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