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Janssen FW, Lak NSM, Janda CY, Kester LA, Meister MT, Merks JHM, van den Heuvel-Eibrink MM, van Noesel MM, Zsiros J, Tytgat GAM, Looijenga LHJ. A comprehensive overview of liquid biopsy applications in pediatric solid tumors. NPJ Precis Oncol 2024; 8:172. [PMID: 39097671 PMCID: PMC11297996 DOI: 10.1038/s41698-024-00657-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 07/15/2024] [Indexed: 08/05/2024] Open
Abstract
Liquid biopsies are emerging as an alternative source for pediatric cancer biomarkers with potential applications during all stages of patient care, from diagnosis to long-term follow-up. While developments within this field are reported, these mainly focus on dedicated items such as a specific liquid biopsy matrix, analyte, and/or single tumor type. To the best of our knowledge, a comprehensive overview is lacking. Here, we review the current state of liquid biopsy research for the most common non-central nervous system pediatric solid tumors. These include neuroblastoma, renal tumors, germ cell tumors, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma and other soft tissue sarcomas, and liver tumors. Within this selection, we discuss the most important or recent studies involving liquid biopsy-based biomarkers, anticipated clinical applications, and the current challenges for success. Furthermore, we provide an overview of liquid biopsy-based biomarker publication output for each tumor type based on a comprehensive literature search between 1989 and 2023. Per study identified, we list the relevant liquid biopsy-based biomarkers, matrices (e.g., peripheral blood, bone marrow, or cerebrospinal fluid), analytes (e.g., circulating cell-free and tumor DNA, microRNAs, and circulating tumor cells), methods (e.g., digital droplet PCR and next-generation sequencing), the involved pediatric patient cohort, and proposed applications. As such, we identified 344 unique publications. Taken together, while the liquid biopsy field in pediatric oncology is still behind adult oncology, potentially relevant publications have increased over the last decade. Importantly, steps towards clinical implementation are rapidly gaining ground, notably through validation of liquid biopsy-based biomarkers in pediatric clinical trials.
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Affiliation(s)
| | | | | | | | - Michael T Meister
- Princess Máxima Center, Utrecht, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Johannes H M Merks
- Princess Máxima Center, Utrecht, the Netherlands
- Division of Imaging and Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Marry M van den Heuvel-Eibrink
- Princess Máxima Center, Utrecht, the Netherlands
- Wilhelmina Children's Hospital-Division of CHILDHEALTH, University Medical Center Utrech, University of Utrecht, Utrecht, the Netherlands
| | - Max M van Noesel
- Princess Máxima Center, Utrecht, the Netherlands
- Division of Imaging and Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | | | - Godelieve A M Tytgat
- Princess Máxima Center, Utrecht, the Netherlands
- Department of Genetics, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands
| | - Leendert H J Looijenga
- Princess Máxima Center, Utrecht, the Netherlands.
- Department of Pathology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
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Liang Y, Liu Y, Zhang P, Zhang M, Du B, Cheng W, Yu Z, Li L, Wang H, Hou G, Zhang X, Zhang W. Plasma circulating cell-free MYCN gene: A noninvasive and prominent recurrence monitoring indicator of neuroblastoma. Cancer Rep (Hoboken) 2023; 6:e1688. [PMID: 35892165 PMCID: PMC9939986 DOI: 10.1002/cnr2.1688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 06/24/2022] [Accepted: 07/12/2022] [Indexed: 11/12/2022] Open
Abstract
The postoperative recurrence of neuroblastoma (NB) patients is an essential reason for the high mortality of NB due to the lack of early, non-invasive, and dynamic strategies for monitoring NB recurrence. Therefore, whether the plasma circulating cell-free MYCN gene as an indicator for monitoring of NB recurrence was systematically evaluated. The MYCN copy number and NAGK (reference gene) copy number (M/N) ratio in plasma and corresponding tumor tissues of NB patients was detected using an economical, sensitive, and specific single-tube dual RT-PCR approach developed in this study. The plasma M/N ratio of the MYCN gene amplification (MNA) group (N = 25, median M/N ratio = 4.90) was significantly higher than that of the non-MNA group (N = 71, median M/N ratio = 1.22), p < .001. The M/N ratio in NB plasma (N = 60) was positively correlated with the M/N ratio in NB tumor tissue (N = 60), with a correlation coefficient of 0.9496. In particular, the results of dynamic monitoring of postoperative plasma M/N ratio of NB patients showed that an abnormal increase in M/N ratio could be detected 1-2 months before recurrence in NB patients. In summary, the single-tube double RT-PCR approach can be used to quantitatively detect MYCN copy number. The copy number of MYCN in the tissue and plasma of NB patients is consistent with each other. More importantly, the circulating cell-free MYCN gene of NB patients can be used as a monitoring indicator for early, non-invasive, and dynamic monitoring of NB recurrence.
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Affiliation(s)
- Ying Liang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Yan Liu
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Pin Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Mengxin Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Bang Du
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Weyland Cheng
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Zhidan Yu
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Lifeng Li
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Huanmin Wang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Guangjun Hou
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Xianwei Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
| | - Wancun Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Key Laboratory of Precise Diagnosis and Treatment of Children's Malignant TumorsChildren's Hospital Affiliated to Zhengzhou UniversityZhengzhouChina
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Zhuo Z, Lin L, Miao L, Li M, He J. Advances in liquid biopsy in neuroblastoma. FUNDAMENTAL RESEARCH 2022; 2:903-917. [PMID: 38933377 PMCID: PMC11197818 DOI: 10.1016/j.fmre.2022.08.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 10/15/2022] Open
Abstract
Even with intensive treatment of high-risk neuroblastoma (NB) patients, half of high-risk NB patients still relapse. New therapies targeting the biological characteristics of NB have important clinical value for the personalized treatment of NB. However, the current biological markers for NB are mainly analyzed by tissue biopsy. In recent years, circulating biomarkers of NB based on liquid biopsy have attracted more and more attention. This review summarizes the analytes and methods for liquid biopsy of NB. We focus on the application of liquid biopsy in the diagnosis, prognosis assessment, and monitoring of NB. Finally, we discuss the prospects and challenges of liquid biopsy in NB.
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Affiliation(s)
- Zhenjian Zhuo
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
- Laboratory Animal Center, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen 518055, China
| | - Lei Lin
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Lei Miao
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Meng Li
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
| | - Jing He
- Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China
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Liang Y, Wang Q, Zhang X, Zhang M, Du B, Cheng W, Wang H, Li L, Hou G, Zhang W. Dual isothermal amplification all-in-one approach for rapid and highly sensitive quantification of plasma circulating MYCN gene of neuroblastoma. Anal Biochem 2022; 658:114922. [PMID: 36162447 DOI: 10.1016/j.ab.2022.114922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 09/16/2022] [Accepted: 09/18/2022] [Indexed: 11/27/2022]
Abstract
A dual isothermal amplification assay with dual fluorescence signal detection strategy, named dual isothermal amplification all-in-one approach, was developed for rapid, one-step, highly sensitive quantification of plasma circulating MYCN copy number of neuroblastoma (NB). The developed strategy consisted of rolling circle amplification (RCA) and loop-mediated isothermal amplification (LAMP) on a real-time PCR system using highly specific probe, molecular beacon (MB), as detection probe. The developed strategy possessing a broad linear dynamic range of 10 aM to 1 pM for both target gene (MYCN) and reference gene (NAGK). The ratio of the MYCN copy number to NAGK copy number (M/N ratio) was detected by the developed approach in cell lines, NB tumor tissues, hepatoblastoma tumor tissues and Wilms' tumor tissues, to which the M/N ratios were consistent with previous reports. In particular, the M/N ratio in NB clinical tissue specimens and NB plasma specimens detected with the developed approach were in keeping with the standard RT-PCR approach. More importantly, the M/N ratio in NB tissue samples and corresponding plasma samples of NB patients were consistent with each other with a correlation coefficient of 0.9690, indicating that plasma circulating MYCN is a promising indicator for the risk classification of NB.
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Affiliation(s)
- Ying Liang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Qionglin Wang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Xianwei Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Mengxin Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Bang Du
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Weyland Cheng
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Huanmin Wang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China
| | - Lifeng Li
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
| | - Guangjun Hou
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
| | - Wancun Zhang
- Henan Key Laboratory of Children's Genetics and Metabolic Diseases, Henan International Joint Laboratory for Pediatric Disease Prevention and Control, Children's Hospital Affiliated to Zhengzhou University, Zhengzhou, 450018, China.
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Yang Y, Zhao J, Zhang Y, Feng T, Yv B, Wang J, Gao Y, Yin M, Tang J, Li Y. MYCN protein stability is a better prognostic indicator in neuroblastoma. BMC Pediatr 2022; 22:404. [PMID: 35820898 PMCID: PMC9277955 DOI: 10.1186/s12887-022-03449-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Accepted: 06/23/2022] [Indexed: 11/17/2022] Open
Abstract
Objective MYCN oncogene amplification is associated with treatment failure and poor prognosis in neuroblastoma. To date, most detection methods of MYCN focus on DNA copy numbers instead of protein expression, which is the real one performing biological function, for poor antibodies. The current investigation was to explore a fast and reliable way to detect MYCN protein expression and evaluate its performance in predicting prognosis. Methods Several MYCN antibodies were used to detect MYCN protein expression by immunohistochemistry (IHC), and one was chosen for further study. We correlated the IHC results of MYCN from 53 patients with MYCN fluorescence in situ hybridization (FISH) and identified the sensitivity and specificity of IHC. The relationship between patient prognosis and MYCN protein expression was detected from this foundation. Results MYCN amplification status detected by FISH was most valuable for INSS stage 3 patients. In the cohort of 53 samples, IHC test demonstrated 80.0–85.7% concordance with FISH results. Further analyzing those cases with inconsistent results, we found that patients with MYCN amplification but low protein expression tumors always had a favorable prognosis. In contrast, if patients with MYCN non-amplified tumors were positive for MYCN protein, they had a poor prognosis. Conclusion MYCN protein level is better than MYCN amplification status in predicting the prognosis of neuroblastoma patients. Joint of FISH and IHC could confirm MYCN protein stability and achieve better prediction effect than the singular method. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-022-03449-1. The MYCN gene test is most valuable for INSS stage 3 patients to predict prognosis. Compared to gene status, MYCN protein expression is more relevant to prognosis. Combining FISH with IHC, MYCN protein stability could be identified.
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Affiliation(s)
- Yi Yang
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China
| | - Jie Zhao
- Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China
| | - Yingwen Zhang
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China
| | - Tianyue Feng
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China.,Gezhi Senior High School of Shanghai China, Shanghai, 200001, China
| | - Bo Yv
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China
| | - Jing Wang
- Department of general Surgery/Surgical Oncology Center, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China
| | - Yijin Gao
- Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China.
| | - Minzhi Yin
- Department of Pathology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.
| | - Jingyan Tang
- Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China.
| | - Yanxin Li
- Pediatric Translational Medicine Institute, Department of Hematology & Oncology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology, Shanghai, 200127, China.
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Liquid biomarkers for the management of paediatric neuroblastoma: an approach to personalised and targeted cancer therapy. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396920000102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
AbstractBackground:Neuroblastoma is the most common extracranial solid tumour of infancy and accounts for about 6–10% of paediatric cancers. It has a biologically and clinically heterogeneous behaviour that ranges from spontaneous regression to cases of highly aggressive metastatic disease that could be unresponsive to standard therapy. In recent years, there have been several investigations into the development of various diagnostic, predictive and prognostic biomarkers towards personalised and targeted management of the disease.Materials and Methods:This paper reports on the review of current clinical and emerging biomarkers used in risk assessment, screening for early detection and diagnosis, prognostication and monitoring of the response of treatment of neuroblastoma in paediatric patients.Conclusions:Tumour markers can significantly improve diagnosis; however, the invasive, unpleasant and inconvenient nature of current tissue biopsies limits their applications, especially in paediatric patients. Therefore, the development of a non-invasive, reliable high accurate and personalised diagnostic tool capable of early detection and rapid response is the most promising step towards advanced cancer management from tumour diagnosis, therapy to patient monitoring and represents an important step towards the promise of precision, personalised and targeted medicine. Liquid biopsy assay with wide ranges of clinical applications is emerging to hold incredible potential for advancing cancer treatment and has greater promise for diagnostic purposes, identification and tracking of tumour-specific alterations during the course of the disease and to guide therapeutic decisions.
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Wei M, Ye M, Dong K, Dong R. Circulating tumor DNA in neuroblastoma. Pediatr Blood Cancer 2020; 67:e28311. [PMID: 32729220 DOI: 10.1002/pbc.28311] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 03/10/2020] [Accepted: 03/19/2020] [Indexed: 12/20/2022]
Abstract
As a sympathetic nervous system-derived tumor, aggressive neuroblastoma (NB) is currently attracting interest from researchers seeking diagnostic and prognostic markers via less invasive procedures. The analysis of circulating tumor DNA (ctDNA) in peripheral blood can provide genetic information from multiple tumor lesions and is not dependent on a surgical procedure. The identification of genetic alterations, chromosomal variations, and hypermethylation contained within plasma DNA yields clinical value in the diagnosis, risk stratification, monitoring of treatment effects, and survival prediction for patients. With the widespread application of genome sequencing, droplet digital polymerase chain reaction, and other advanced technologies, the detection of ctDNA may guide therapeutic schedules, enhance the quality of life, and improve the prognosis for patients with NB.
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Affiliation(s)
- Meng Wei
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Mujie Ye
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Kuiran Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
| | - Rui Dong
- Department of Pediatric Surgery, Children's Hospital of Fudan University, Shanghai, China
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Diagnostic accuracy of circulating-free DNA for the determination of MYCN amplification status in advanced-stage neuroblastoma: a systematic review and meta-analysis. Br J Cancer 2020; 122:1077-1084. [PMID: 32015512 PMCID: PMC7109036 DOI: 10.1038/s41416-020-0740-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2019] [Revised: 12/20/2019] [Accepted: 01/15/2020] [Indexed: 11/25/2022] Open
Abstract
Background MYCN amplification (MNA) is the strongest indicator of poor prognosis in neuroblastoma (NB). This meta-analysis aims to determine the diagnostic accuracy of MNA analysis in circulating-free DNA (cfDNA) from advanced-stage NB patients. Methods A systematic review of electronic databases was conducted to identify studies exploring the detection of MNA in plasma/serum cfDNA from NB patients at diagnosis using PCR methodology. Pooled estimates for sensitivity, specificity and diagnostic odds ratio (DOR) were calculated by conducting a bivariate/HSROC random-effects meta-analysis. Results Seven studies, with a total of 529 advanced-stage patients, were eligible. The pooled sensitivity of cfDNA-based MNA analysis was 0.908 (95% CI, 0.818–0.956), the pooled specificity was 0.976 (0.940–0.991) and the DOR was 410.0 (−103.6 to 923.7). Sub-grouped by INSS stage, the sensitivity for stage 3 and 4 patients was 0.832 (0.677–0.921) and 0.930 (0.834–0.972), respectively. The specificity was 0.999 (0.109–1.000) and 0.974 (0.937–0.990), respectively, and the DOR was 7855.2 (−66267.0 to 81977.4) and 508.7 (−85.8 to 1103.2), respectively. Conclusions MNA analysis in cfDNA using PCR methodology represents a non-invasive approach to rapidly and accurately determine MNA status in patients with advanced-stage NB. Standardised methodology must be developed before this diagnostic test can enter the clinic.
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Trigg RM, Shaw JA, Turner SD. Opportunities and challenges of circulating biomarkers in neuroblastoma. Open Biol 2019; 9:190056. [PMID: 31088252 PMCID: PMC6544987 DOI: 10.1098/rsob.190056] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Accepted: 04/23/2019] [Indexed: 12/11/2022] Open
Abstract
Molecular analysis of nucleic acid and protein biomarkers is becoming increasingly common in paediatric oncology for diagnosis, risk stratification and molecularly targeted therapeutics. However, many current and emerging biomarkers are based on analysis of tumour tissue, which is obtained through invasive surgical procedures and in some cases may not be accessible. Over the past decade, there has been growing interest in the utility of circulating biomarkers such as cell-free nucleic acids, circulating tumour cells and extracellular vesicles as a so-called liquid biopsy of cancer. Here, we review the potential of emerging circulating biomarkers in the management of neuroblastoma and highlight challenges to their implementation in the clinic.
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Affiliation(s)
- Ricky M. Trigg
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
| | - Jacqui A. Shaw
- Leicester Cancer Research Centre, College of Life Sciences, University of Leicester, Leicester LE2 7LX, UK
| | - Suzanne D. Turner
- Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge CB2 0QQ, UK
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