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Xue Y, Huang C, Pei B, Wang Z, Dai Y. An overview of DNA methylation markers for early detection of gastric cancer: current status, challenges, and prospects. Front Genet 2023; 14:1234645. [PMID: 37560387 PMCID: PMC10407555 DOI: 10.3389/fgene.2023.1234645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/17/2023] [Indexed: 08/11/2023] Open
Abstract
Background: Gastric cancer (GC) is one of the most common malignancies, with a low 5-year survival rate. However, if diagnosed at an early stage, it can be cured by endoscopic treatment and has a good prognosis. While gastrointestinal X-ray and upper endoscopy are used as national GC screening methods in some GC high-risk countries, such as Japan and Korea, their radiation exposure, invasiveness, and high cost suggest that they are not the optimal tools for early detection of GC in many countries. Therefore, a cost-effective, and highly accurate method for GC early detection is urgently needed in clinical settings. DNA methylation plays a key role in cancer progression and metastasis and has been demonstrated as a promising marker for cancer early detection. Aims and methods: This review provides a comprehensive overview of the current status of DNA methylation markers associated with GC, the assays developed for GC early detection, challenges in methylation marker discovery and application, and the future prospects of utilizing methylation markers for early detection of GC. Through our analysis, we found that the currently reported DNA methylation markers related to GC are mainly in the early discovery stage. Most of them have only been evaluated in tissue samples. The majority of non-invasive assays developed based on blood lack standardized sampling protocols, pre-analytical procedures, and multicenter validation, and they exhibit insufficient sensitivity for early-stage GC detection. Meanwhile, the reported GC DNA methylation markers are generally considered pan-cancer markers. Conclusion: Therefore, future endeavors should focus on identifying additional methylation markers specific to GC and establishing non-invasive diagnostic assays that rely on these markers. These assays should undergo multicenter, large-scale prospective validation in diverse populations.
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Affiliation(s)
- Ying Xue
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Chao Huang
- The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, China
| | - Bing Pei
- Department of Clinical Laboratory, The Affiliated Suqian First People’s Hospital of Nanjing Medical University, Suqian, Jiangsu, China
| | - ZhenZhen Wang
- Department of Laboratory Medicine, Affiliated Xuzhou Maternity and Child Healthcare Hospital of Xuzhou Medical University, Xuzhou, China
| | - Yanmiao Dai
- Department of Spleen and Stomach Diseases, Kunshan Hospital of Traditional Chinese Medicine, Kunshan, China
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Zhai J, Sun H, Li M, Gao Y, Hu Y, Gao Z, Xie X, Zhang L, Zhao G. Simple and sensitive detection of miRNA-122 based on a micro-biosensor through square wave voltammetry. RSC Adv 2023; 13:21414-21420. [PMID: 37465577 PMCID: PMC10350789 DOI: 10.1039/d3ra03759b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 07/12/2023] [Indexed: 07/20/2023] Open
Abstract
The simple and sensitive detection of miRNA-122 in blood is crucially important for early hepatocellular carcinoma (HCC) diagnosis. In this work, a platinum microelectrode (PtμE) was prepared and electrodeposited with molybdenum disulfide (MoS2) and gold nanoparticles (AuNP), respectively, and denoted as PtμE/MoS2/Au. The prepared PtμE/MoS2/Au was used as the microsensor for the detection of miRNA-122 combined with the probe DNA as a biorecognition element which is the complementary strand of miRNA-122. The PtμE/MoS2/Au conjugated with the probe DNA modified with sulfydryl units was used as the micro-biosensor for the detection of miRNA-122. The square wave voltammetry was performed for the quantitative detection of miRNA-122 using [Fe(CN)6]4-/3- as a mediator. Under the optimized conditions, the PtμE/MoS2/Au micro-biosensor shows a linear detection toward miRNA-122 ranging from 10-11 to 10-8 M (S = 6.9 nA dec-1, R2 = 0.9997), and the detection limit is 1.6 × 10-12 M (3σ/b). The PtμE/MoS2/Au micro-biosensor demonstrates good selectivity against other types of proteins and small molecules, and has good reproducibility. Moreover, the PtμE/MoS2/Au micro-biosensor was successfully applied for the measurement of miRNA-122 in real blood samples. Herein, the proposed detection assay could be a potential tool in HCC clinical diagnostics with high sensitivity.
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Affiliation(s)
- Jiali Zhai
- School of Rehabilitation Medicine of Binzhou Medical University Yantai 264003 China +86 535 6913246 +86 535 6913213
| | - Huiyuan Sun
- Department of Critical Care Medicine, Yantai Yuhuangding Hospital Yantai 264003 China
| | - Mingkang Li
- The 2nd Medical College of Binzhou Medical University Yantai 264003 China
| | - Yuhao Gao
- The 2nd Medical College of Binzhou Medical University Yantai 264003 China
| | - Yixin Hu
- The 2nd Medical College of Binzhou Medical University Yantai 264003 China
| | - Zhi Gao
- Academy of Traditional Chinese and Western Medicine of Binzhou Medical University Yantai 264003 China
| | - Xiyu Xie
- Academy of Traditional Chinese and Western Medicine of Binzhou Medical University Yantai 264003 China
| | - Lixia Zhang
- School of Basic Medicine, Binzhou Medical University Yantai 264003 China
| | - Guangtao Zhao
- School of Basic Medicine, Binzhou Medical University Yantai 264003 China
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Patrick-Brown TD, Mohamed F, Thrower A, Torgunrud A, Cosyns S, Canbay E, Villeneuve L, Flatmark K, Brandl A. Determining a minimum data set for reporting clinical and radiologic data for pseudomyxoma peritonei. Pleura Peritoneum 2023; 8:1-9. [PMID: 37020469 PMCID: PMC10067554 DOI: 10.1515/pp-2022-0200] [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: 10/25/2022] [Accepted: 02/22/2023] [Indexed: 04/05/2023] Open
Abstract
Objectives Pseudomyxoma peritonei (PMP) is a rare cancer currently affecting over 11,736 patients across Europe. Since PMP is so uncommon, collaboration between scientific centers is key to discovering the mechanisms behind the disease, efficient treatments, and targets pointing to a cure. To date, no consensus has been reached on the minimum data that should be collected during PMP research studies. This issue has become more important as biobanking becomes the norm. This paper begins the discussion around a minimum data set that should be collected by researchers through a review of available clinical trial reports in order to facilitate collaborative efforts within the PMP research community. Content A review of articles from PubMed, CenterWatch, ClinicalTrials.gov and MedRxiv was undertaken, and clinical trials reporting PMP results selected. Summary There is a core set of data that researchers report, including age and sex, overall survival, peritoneal cancer index (PCI) score, and completeness of cytoreduction, but after this, reports become variable. Outlook Since PMP is a rare disease, it is important that reports include as large of a number of standardised data points as possible. Our research indicates that there is still much ground to cover before this becomes a reality.
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Affiliation(s)
| | - Faheez Mohamed
- Peritoneal Malignancy Institute, Basingstoke Hospital, Basingstoke, UK
| | - Andrew Thrower
- Hampshire Hospitals NHS Foundation, Basingstoke Hospital, Basingstoke, UK
| | - Annette Torgunrud
- Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Sarah Cosyns
- Cancer Research Institute Ghent (CRIG), Ghent University, Ghent, Belgium
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
| | - Emel Canbay
- Department of General Surgery, İstanbul University İstanbul School of Medicine, İstanbul, Türkiye
| | - Laurent Villeneuve
- Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
- Service de Recherche et d’Epidémiologie Cliniques, Hospices Civils de Lyon, Hôpital Lyon Sud, Université Lyon-1, Lyon, France
| | - Kjersti Flatmark
- Department of Tumour Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
- Department of Gastroenterological Surgery, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Andreas Brandl
- Department of Surgery, University Hospital Heidelberg, Heidelberg, Germany
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Ma S, Zhou M, Xu Y, Gu X, Zou M, Abudushalamu G, Yao Y, Fan X, Wu G. Clinical application and detection techniques of liquid biopsy in gastric cancer. Mol Cancer 2023; 22:7. [PMID: 36627698 PMCID: PMC9832643 DOI: 10.1186/s12943-023-01715-z] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 01/02/2023] [Indexed: 01/12/2023] Open
Abstract
Gastric cancer (GC) is one of the most common tumors worldwide and the leading cause of tumor-related mortality. Endoscopy and serological tumor marker testing are currently the main methods of GC screening, and treatment relies on surgical resection or chemotherapy. However, traditional examination and treatment methods are more harmful to patients and less sensitive and accurate. A minimally invasive method to respond to GC early screening, prognosis monitoring, treatment efficacy, and drug resistance situations is urgently needed. As a result, liquid biopsy techniques have received much attention in the clinical application of GC. The non-invasive liquid biopsy technique requires fewer samples, is reproducible, and can guide individualized patient treatment by monitoring patients' molecular-level changes in real-time. In this review, we introduced the clinical applications of circulating tumor cells, circulating free DNA, circulating tumor DNA, non-coding RNAs, exosomes, and proteins, which are the primary markers in liquid biopsy technology in GC. We also discuss the current limitations and future trends of liquid biopsy technology as applied to early clinical biopsy technology.
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Affiliation(s)
- Shuo Ma
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Meiling Zhou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yanhua Xu
- grid.452743.30000 0004 1788 4869Department of Laboratory Medicine, Northern Jiangsu People’s Hospital Affiliated to Yangzhou University, Yangzhou, 225000 Jiangsu China
| | - Xinliang Gu
- grid.440642.00000 0004 0644 5481Department of Laboratory Medicine, Medical School, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001 Jiangsu China
| | - Mingyuan Zou
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Gulinaizhaer Abudushalamu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Yuming Yao
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Xiaobo Fan
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China
| | - Guoqiu Wu
- grid.452290.80000 0004 1760 6316Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Department of Laboratory Medicine, Medical School of Southeast University, Nanjing, 210009 Jiangsu China ,grid.263826.b0000 0004 1761 0489Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, 210009 Jiangsu China
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Zhai J, Ji P, Xin Y, Liu Y, Qu Q, Han W, Zhao G. Development of Carcinoembryonic Antigen Rapid Detection System Based on Platinum Microelectrode. Front Chem 2022; 10:899276. [PMID: 35795222 PMCID: PMC9252266 DOI: 10.3389/fchem.2022.899276] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 05/11/2022] [Indexed: 12/02/2022] Open
Abstract
Rapid and highly sensitive detection of carcinoembryonic antigen (CEA) in blood could effectively improve the diagnostic sensitivity of colorectal cancer. In this work, a platinum microelectrode (PtμE) modified with gold nanoparticles was developed as a microsensor for the detection of CEA. As the recognition element, a CEA aptamer modified with sulfhydryl could be conjugated onto the surface of the PtμEs/Au. The quantitative analysis of the concentration of CEA [CEA] by the prepared PtμEs/Au aptasensor was carried out through square wave voltammetry. Under the optimized conditions, the PtμEs/Au aptasensor exhibits a linear response toward [CEA] in the range of 1.0 × 10–11—1.0 × 10–7 g/ml (S = 5.5 nA/dec, R2 = 0.999), and the detection limit is 7.7 × 10–12 g/ml. The PtμEs/Au aptasensor also has good selectivity against other types of proteins existing in blood. The availability of the developed assay toward [CEA] in blood samples was investigated, and the results agreed well with those obtained through electrochemiluminescence provided by the hospital, and the volume of the blood sample for detection is only 20 μl. Herein, the proposed detection system could be used for the quantitative analysis of CEA in blood, with the advantages of high sensitivity, short time, and low cost. Moreover, the PtμEs/Au aptasensor has a potential application in clinical diagnosis.
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Affiliation(s)
- Jiali Zhai
- School of Rehabilitation Medicine of Binzhou Medical University, Yantai, China
| | - Piyou Ji
- Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Yu Xin
- School of Medical Imaging, Binzhou Medical University, Yantai, China
| | - Yifan Liu
- School of Medical Imaging, Binzhou Medical University, Yantai, China
| | - Qianwen Qu
- School of Medical Imaging, Binzhou Medical University, Yantai, China
| | - Wentong Han
- School of Medical Imaging, Binzhou Medical University, Yantai, China
| | - Guangtao Zhao
- School of Basic Medicine, Binzhou Medical University, Yantai, China
- *Correspondence: Guangtao Zhao,
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Huang ZB, Zhang HT, Yu B, Yu DH. Cell-free DNA as a liquid biopsy for early detection of gastric cancer. Oncol Lett 2021; 21:3. [PMID: 33240409 PMCID: PMC7681206 DOI: 10.3892/ol.2020.12264] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 09/17/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is one of the most common malignant tumors with poor prognosis worldwide, mainly due to the lack of suitable modalities for population-based screening and early detection of this disease. Therefore, novel and less invasive tests with improved clinical utility are urgently required. The remarkable advances in genomics and proteomics, along with emerging new technologies for highly sensitive detection of genetic alterations, have shown the potential to map the genomic makeup of a tumor in liquid biopsies, in order to assist with early detection and clinical management. The present review summarize the current status in the identification and development of cell-free DNA (cfDNA)-based biomarkers in GC, and also discusses their potential utility and the technical challenges in developing practical cfDNA-based liquid biopsy for early detection of GC.
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Affiliation(s)
- Zheng-Bin Huang
- Department of Surgery, Hanchuan Renmin Hospital, Hanchuan, Hubei 431600, P.R. China
| | - Hai-Tao Zhang
- Department of Gastrointestinal Surgery, The Second People's Hospital of Shenzhen, Shenzhen, Guangdong 518037, P.R. China
| | - Benjamin Yu
- Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - De-Hua Yu
- Shenzhen USK Bioscience Co., Ltd., Shenzhen, Guangdong 518110, P.R. China
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Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol 2018; 51:36-49. [PMID: 29253542 PMCID: PMC7286571 DOI: 10.1016/j.semcancer.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/17/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ajay Goel
- Center for Gastrointestinal Research, and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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Kristiansen S, Sölétormos G. Clinical Utility of Solid Tumor Epigenetics. MEDICAL EPIGENETICS 2016:459-471. [DOI: 10.1016/b978-0-12-803239-8.00025-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Chen X, Lin Z, Xue M, Si J, Chen S. Zic1 Promoter Hypermethylation in Plasma DNA Is a Potential Biomarker for Gastric Cancer and Intraepithelial Neoplasia. PLoS One 2015. [PMID: 26207911 PMCID: PMC4514771 DOI: 10.1371/journal.pone.0133906] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common digestive cancers worldwide; however, most patients present at an advanced stage at initial diagnosis. Zic1 is a novel candidate tumor suppressor gene that is epigenetically silenced in GC. In this study, we investigated Zic1 promoter methylation in plasma DNA as a novel molecular marker for the early diagnosis and monitoring of GC. Methylation-specific polymerase chain reaction (MSP) assay was performed to detect Zic1 promoter methylation in plasma DNA from 20 healthy subjects, 50 gastric intraepithelial neoplasia patients, and 104 GC patients. The Zic1 promoter methylation rate in the plasma samples from the healthy control group was 0%, but it reached 54.0% in the intraepithelial neoplasia group and 60.6% in the GC group. The latter two values were significantly higher than that found in the healthy control group (p < 0.05), with a 100% specificity for intraepithelial neoplasia and GC diagnosis. The positive predictive value of plasma Zic1 promoter methylation for the diagnosis of intraepithelial neoplasia and GC was 100%. Methylation status in the GC group was not significantly associated with tumor size, tumor differentiation, lymph node metastasis, TNM staging, or tumor invasion (p > 0.05). Assessment of the significance of detection of the carcino-embryonic antigen (CEA) level and Zic1 promoter methylation rate for GC diagnosis revealed that the sensitivity of Zic1 promoter methylation was significantly higher than that of the CEA level as a marker and that the combined measurement of these two indices (parallel testing) improved sensitivity. Taken together, our results suggest that the Zic1 promoter methylation rate in plasma-derived DNA is of great significance for the early screening of GC and monitoring of tumorigenesis. Zic1 promoter methylation may serve as a novel non-invasive plasma biomarker for the early detection of GC and for risk assessment in high-risk populations. The combined measurement of the Zic1 promoter methylation rate and CEA level (parallel testing) may enhance the current guidelines for the early diagnosis of GC.
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Affiliation(s)
- Xueqin Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Zhenghua Lin
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Meng Xue
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianmin Si
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
| | - Shujie Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, Zhejiang, China
- Institute of Gastroenterology, Zhejiang University, Hangzhou, Zhejiang, China
- * E-mail:
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Tsujiura M, Ichikawa D, Konishi H, Komatsu S, Shiozaki A, Otsuji E. Liquid biopsy of gastric cancer patients: Circulating tumor cells and cell-free nucleic acids. World J Gastroenterol 2014; 20:3265-3286. [PMID: 24696609 PMCID: PMC3964398 DOI: 10.3748/wjg.v20.i12.3265] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/27/2013] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
To improve the clinical outcomes of cancer patients, early detection and accurate monitoring of diseases are necessary. Numerous genetic and epigenetic alterations contribute to oncogenesis and cancer progression, and analyses of these changes have been increasingly utilized for diagnostic, prognostic and therapeutic purposes in malignant diseases including gastric cancer (GC). Surgical and/or biopsy specimens are generally used to understand the tumor-associated alterations; however, those approaches cannot always be performed because of their invasive characteristics and may fail to reflect current tumor dynamics and drug sensitivities, which may change during the therapeutic process. Therefore, the importance of developing a non-invasive biomarker with the ability to monitor real-time tumor dynamics should be emphasized. This concept, so called “liquid biopsy”, would provide an ideal therapeutic strategy for an individual cancer patient and would facilitate the development of “tailor-made” cancer management programs. In the blood of cancer patients, the presence and potent utilities of circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs) such as DNA, mRNA and microRNA have been recognized, and their clinical relevance is attracting considerable attention. In this review, we discuss recent developments in this research field as well as the relevance and future perspectives of CTCs and cfNAs in cancer patients, especially focusing on GC.
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Tänzer M, Liebl M, Quante M. Molecular biomarkers in esophageal, gastric, and colorectal adenocarcinoma. Pharmacol Ther 2013; 140:133-47. [PMID: 23791941 DOI: 10.1016/j.pharmthera.2013.06.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2013] [Accepted: 06/06/2013] [Indexed: 02/06/2023]
Abstract
Cancers of the esophagus, stomach and colon contribute to a major health burden worldwide and over 20% of all cancer deaths. Biomarkers that should indicate pathogenic process and are measureable in an objective manner for these tumors are rare and not established in the clinical setting. In general biomarkers can be very useful for cancer management as they can improve clinical decision-making regarding diagnosis, surveillance, and therapy. Biomarkers can be different types of molecular entities (such as DNA, RNA or proteins), which can be detected, in different tissues or body fluids. However, more important is the type of biomarker itself, which allows diagnostic, prognostic or predictive analyses for different clinical problems. This review aims to systematically summarize the recent findings of genetic and epigenetic markers for gastrointestinal tumors within the last decade. While many biomarkers seem to be very promising, especially if used as panels, further development is urgently needed to address practical considerations of biomarkers in cancer treatment.
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Affiliation(s)
- Marc Tänzer
- II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany
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Development of a quantitative methylation-specific polymerase chain reaction method for monitoring beta cell death in type 1 diabetes. PLoS One 2012; 7:e47942. [PMID: 23144715 PMCID: PMC3483298 DOI: 10.1371/journal.pone.0047942] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2012] [Accepted: 09/25/2012] [Indexed: 01/05/2023] Open
Abstract
DNA methylation is a mechanism by which cells control gene expression, and cell-specific genes often exhibit unique patterns of DNA methylation. We previously reported that the mouse insulin-2 gene (Ins2) promoter has three potential methylation (CpG) sites, all of which are unmethylated in insulin-producing cells but methylated in other tissues. In this study we examined Ins2 exon 2 and found a similar tissue-specific methylation pattern. These methylation patterns can differentiate between DNA from insulin-producing beta cells and other tissues. We hypothesized that damaged beta cells release their DNA into circulation at the onset of type 1 diabetes mellitus (T1DM) and sought to develop a quantitative methylation-specific polymerase chain reaction (qMSP) assay for circulating beta cell DNA to monitor the loss of beta cells. Methylation-specific primers were designed to interrogate two or more CpG in the same assay. The cloned mouse Ins2 gene was methylated in vitro and used for development of the qMSP assay. We found the qMSP method to be sensitive and specific to differentiate between insulin-producing cells and other tissues with a detection limit of 10 copies in the presence of non-specific genomic DNA background. We also compared different methods for data analysis and found that the Relative Expression Ratio method is the most robust method since it incorporates both a reference value to normalize day-to-day variability as well as PCR reaction efficiencies to normalize between the methylation-specific and bisulfite-specific components of the calculations. The assay was applied in the streptozotocin-treated diabetic mouse model and detected a significant increase in circulating beta cell DNA before the rise in blood glucose level. These results demonstrate that this qMSP assay can be used for monitoring circulating DNA from insulin-producing cells, which will provide the basis for development of assays to detect beta cell destruction in early T1DM.
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Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications. Surg Today 2010; 41:24-38. [DOI: 10.1007/s00595-010-4370-5] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2010] [Accepted: 04/22/2010] [Indexed: 02/07/2023]
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Promoter hypermethylation of KiSS-1 gene in gastric cancer. Chin J Cancer Res 2010. [DOI: 10.1007/s11670-010-0280-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022] Open
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15
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Takeshita H, Ichikawa D, Komatsu S, Tsujiura M, Kosuga T, Deguchi K, Konishi H, Morimura R, Shiozaki A, Fujiwara H, Okamoto K, Otsuji E. Prediction of CCND1 amplification using plasma DNA as a prognostic marker in oesophageal squamous cell carcinoma. Br J Cancer 2010; 102:1378-83. [PMID: 20389301 PMCID: PMC2865765 DOI: 10.1038/sj.bjc.6605657] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Background: We aimed to develop a new biomarker to predict cyclin D1 (CCND1) status using plasma DNA in oesophageal squamous cell carcinoma (ESCC) patients. Methods: We evaluated the ratio of the CCND1 (11q13) dosage to the dopamine receptor D2 (DRD2; 11q22-23) dosage (C/D ratio) as CCND1 copy number. This study was divided into three steps: (1) Determination of a cutoff value for the C/D ratio in test scale; (2) Comparison of the C/D ratio in between plasma samples and cancer tissues in ESCC patients showing high plasma C/D ratio; (3) Validation study of the clinical application of the plasma C/D ratio as a diagnostic and prognostic marker, by comparing with clinicopathologic factors in 96 ESCC patients. Results: The plasma C/D ratio was significantly higher in the ESCC group than the controls (P=0.0134). A high plasma C/D ratio reflected the tumour C/D ratio, and significantly correlated with a poorer prognosis (P=0.0186). Moreover, the high C/D ratio was found to be an independent prognostic factor on multivariate analysis (P=0.0266; hazard ratio 5.988). Conclusion: Prediction of CCND1 amplification using plasma DNA is thought to be a promising prognostic biomarker in ESCC patients.
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Affiliation(s)
- H Takeshita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachihirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
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Shivapurkar N, Gazdar AF. DNA methylation based biomarkers in non-invasive cancer screening. Curr Mol Med 2010; 10:123-32. [PMID: 20196733 PMCID: PMC3397200 DOI: 10.2174/156652410790963303] [Citation(s) in RCA: 88] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2008] [Accepted: 05/10/2009] [Indexed: 12/31/2022]
Abstract
DNA methylation plays a critical role in the regulation of gene expression, differentiation and in the development of cancer and other diseases. Hypermethylation of CpG islands located in the promoter regions of tumor suppressor genes is now firmly established as the most frequent mechanism for gene inactivation in cancers. Feasibility of using DNA methylation based biomarkers for early detection of cancer has been shown. Potential of using DNA methylation for prediction of therapeutic outcome and patient survival has also been shown. DNA originated from cancer cells has been routinely detected in clinical specimens (ex. Plasma/serum, sputum, urine etc.) from cancer patients. Presence of methylated DNA sequences in clinical specimens and potential of using them as biomarkers have been recognized. Novel methylation based biomarkers that can be used in clinical specimens, obtained non-invasively from cancer patients, offer significant practical advantages. More resources need to be committed to this area of biomarker research. Thus, we review recent findings on DNA methylation based cancer biomarkers with particular focus on these applicable to the clinical specimens obtained non-invasively from cancer patients.
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Affiliation(s)
- N Shivapurkar
- Hamon Center for Therapeutic Oncology Research, University of Texas, Southwestern Medical Center, Dallas, TX 75390, USA.
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Kamiyama H, Noda H, Takata O, Suzuki K, Kawamura Y, Konishi F. Promoter hypermethylation of tumor-related genes in peritoneal lavage and the prognosis of patients with colorectal cancer. J Surg Oncol 2009; 100:69-74. [PMID: 19384904 DOI: 10.1002/jso.21291] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND OBJECTIVES The predictive value of free cancer cells in the peritoneal fluid of patients with colorectal cancer (CRC) remain to be elucidated. The aim of this study was to determine the prognostic relevance of the methylation of tumor-related genes detected in the peritoneal lavage fluid (PLF) of patients undergoing a resection for CRC. METHODS The promoter methylation pattern of four target genes, CDH1, CDKN2A (p16), MGMT, and APC, was examined in 51 primary CRC and corresponding matched PLF DNA. The relative methylation levels of these genes in primary CRC tissue and paired PLF were assessed by quantitative methylation-specific polymerase chain reaction (QMSP). RESULTS An aberrant methylation of at least one gene was found in 45 of 51 (88%) primary tumors. In matched PLF specimens, the frequencies of aberrant promoter methylation detected for each marker were 16% for CDH1, 2% for p16, 4% for MGMT and 24% for APC. Patients with PLF demonstrating the methylation of more than one of these four target genes demonstrated significantly shorter relapse-free survival. CONCLUSIONS These findings suggest that disseminated tumor cells in PLF detected by QMSP may correlate with the postoperative clinical course of patients undergoing curative surgery for CRC.
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Affiliation(s)
- Hidenori Kamiyama
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Japan
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Watanabe Y, Kim HS, Castoro RJ, Chung W, Estecio MRH, Kondo K, Guo Y, Ahmed SS, Toyota M, Itoh F, Suk KT, Cho MY, Shen L, Jelinek J, Issa JPJ. Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes. Gastroenterology 2009; 136:2149-58. [PMID: 19375421 PMCID: PMC2722957 DOI: 10.1053/j.gastro.2009.02.085] [Citation(s) in RCA: 100] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2008] [Revised: 02/21/2009] [Accepted: 02/26/2009] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Aberrant DNA methylation is an early and frequent process in gastric carcinogenesis and could be useful for detection of gastric neoplasia. We hypothesized that methylation analysis of DNA recovered from gastric washes could be used to detect gastric cancer. METHODS We studied 51 candidate genes in 7 gastric cancer cell lines and 24 samples (training set) and identified 6 for further studies. We examined the methylation status of these genes in a test set consisting of 131 gastric neoplasias at various stages. Finally, we validated the 6 candidate genes in a different population of 40 primary gastric cancer samples and 113 nonneoplastic gastric mucosa samples. RESULTS Six genes (MINT25, RORA, GDNF, ADAM23, PRDM5, MLF1) showed frequent differential methylation between gastric cancer and normal mucosa in the training, test, and validation sets. GDNF and MINT25 were most sensitive molecular markers of early stage gastric cancer, whereas PRDM5 and MLF1 were markers of a field defect. There was a close correlation (r = 0.5-0.9, P = .03-.001) between methylation levels in tumor biopsy and gastric washes. MINT25 methylation had the best sensitivity (90%), specificity (96%), and area under the receiver operating characteristic curve (0.961) in terms of tumor detection in gastric washes. CONCLUSIONS These findings suggest MINT25 is a sensitive and specific marker for screening in gastric cancer. Additionally, we have developed a new method for gastric cancer detection by DNA methylation in gastric washes.
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Affiliation(s)
- Yoshiyuki Watanabe
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Hyun Soo Kim
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Ryan J. Castoro
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Woonbok Chung
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | | | - Kimie Kondo
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Yi Guo
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Saira S. Ahmed
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Minoru Toyota
- First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
| | - Fumio Itoh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan
| | - Ki Tae Suk
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Mee-Yon Cho
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Lanlan Shen
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Jaroslav Jelinek
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
| | - Jean-Pierre J. Issa
- Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
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19
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He H, Chen G, Zhou L, Liu Y. A joint detection of CEA and CA-50 levels in saliva and serum of patients with tumors in oral region and salivary gland. J Cancer Res Clin Oncol 2009; 135:1315-21. [PMID: 19322585 DOI: 10.1007/s00432-009-0572-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2008] [Accepted: 03/09/2009] [Indexed: 11/24/2022]
Abstract
OBJECTIVE To detect the levels of carcinoembryonic antigen (CEA) and carcinoma associated antigen CA-50 in the patients with oral or salivary malignant tumors. METHODS The concentrations of salivary CEA and CA-50 were assayed in 80 patients of oral and salivary malignant tumors, 40 patients of benign tumors and 80 health controls. In 80 patients with malignant tumors, serum CEA and CA-50 were also assayed by enzyme-linked immunoabsorbent assay and immunoradiometric analysis, respectively. RESULTS Salivary CEA and CA-50 levels were significantly higher in malignant tumors than in benign tumors and in health controls, respectively (P < 0.001). Only 7 cases and 3 cases of 80 patients with malignant tumors were found having increased serum CEA and CA-50 levels, respectively. CONCLUSIONS The measurement of CEA and CA-50 levels in saliva were more sensitive than in serum. This may be more useful as prognostic indicators in early diagnosis of oral and salivary malignant tumors.
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Affiliation(s)
- Hong He
- Department of Stomatology, Second Affiliated Hospital, Medicine School, Zhejiang University, 310009 Hangzhou, China
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20
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Cheng YY, Yu J, Wong YP, Man EPS, To KF, Jin VX, Li J, Tao Q, Sung JJY, Chan FKL, Leung WK. Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer. Br J Cancer 2007; 97:895-901. [PMID: 17848950 PMCID: PMC2360406 DOI: 10.1038/sj.bjc.6603968] [Citation(s) in RCA: 99] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The role of secreted frizzled-related protein (SFRP) genes in gastric cancer remains largely unknown. We determined the frequency and functional significance of SFRPs hypermethylation in human gastric cancer. The expression and methylation status of four SFRP members (SFRP1, 2, 4, and 5) in primary gastric cancer samples was screened. The biological effects of SFRP were analysed by flow cytometry, cell viability assay and in vivo tumour growth in nude mice. Among the four SFRPs, only SFRP2 was significantly downregulated in gastric cancer as compared to adjacent non-cancer samples (P<0.01). Promoter hypermethylation of SFRP2 was detected in 73.3% primary gastric cancer tissues, 37.5% of samples showing intestinal metaplasia and 20% adjacent normal gastric tissues. Bisulphite DNA sequencing confirmed the densely methylated SFRP2 promoter region. Demethylation treatment restored the expression of SFRP2 in gastric cancer cell lines. Forced expression of SFRP2 induced cell apoptosis, inhibited proliferation of gastric cancer cells and suppressed tumour growth in vivo. Moreover, methylated SFRP2 was detected in 66.7% of serum samples from cancer patients but not in normal controls. In conclusion, epigenetic inactivation of SFRP2 is a common and early event contributing to gastric carcinogenesis and may be a potential biomarker for gastric cancer.
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Affiliation(s)
- Y Y Cheng
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - J Yu
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Y P Wong
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - E P S Man
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - K F To
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
| | - V X Jin
- Department of Pharmacology and the Genome Center, University of California-Davis, CA, USA
| | - J Li
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Q Tao
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Department of Clinical Oncology, The Chinese University of Hong Kong, Hong Kong, China
| | - J J Y Sung
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - F K L Chan
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - W K Leung
- Institute of Digestive Disease, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory in Oncology in South China, The Chinese University of Hong Kong, Hong Kong, China
- Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China. E-mail:
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Fleischhacker M, Schmidt B. Circulating nucleic acids (CNAs) and cancer--a survey. Biochim Biophys Acta Rev Cancer 2006; 1775:181-232. [PMID: 17137717 DOI: 10.1016/j.bbcan.2006.10.001] [Citation(s) in RCA: 422] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2006] [Revised: 10/04/2006] [Accepted: 10/04/2006] [Indexed: 12/23/2022]
Abstract
It has been known for decades that it is possible to detect small amounts of extracellular nucleic acids in plasma and serum of healthy and diseased human beings. The unequivocal proof that part of these circulating nucleic acids (CNAs) is of tumor origin, initiated a surge of studies which confirmed and extended the original observations. In the past few years many experiments showed that tumor-associated alterations can be detected at the DNA and RNA level. At the DNA level the detection of point mutations, microsatellite alterations, chromosomal alterations, i.e. inversion and deletion, and hypermethylation of promoter sequences were demonstrated. At the RNA level the overexpression of tumor-associated genes was shown. These observations laid the foundation for the development of assays for an early detection of cancer as well as for other clinical means.
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Affiliation(s)
- M Fleischhacker
- Charité, Universitätsmedizin Berlin, Medizinische Klinik mS Onkologie u Hämatologie, CCM, Charitéplatz 1, 10117 Berlin, Germany.
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Abstract
Gastric cancer affects annually more than 800,000 individuals worldwide and remains a challenge for clinicians and oncologists. Most patients with gastric cancer are diagnosed in advanced stages, when a curative resection is impossible, which leads to an overall poor prognosis. Finding new diagnostic and treatment procedures is of paramount importance to improve patient prognosis, which will be improved most dramatically by techniques that allow the detection of gastric cancer in its early stages. So far the value of conventional tumour markers such as Ca72-4 or carcinoembryonic antigen is limited, and even markers developed from molecular biological studies on the carcinogenesis of gastric cancer, such as E-cadherin and others, have not proved to be of adequate sensitivity and specificity to allow the early detection of gastric cancer. With the development of innovative diagnostic tools, such as proteome analysis, new biomarkers may be identified that may allow early diagnosis and thus screening for gastric cancer, particularly in at-risk patient populations. Recent studies have indicated that these biomarkers may be derived from the tumour itself or reflect a specific metabolic or immunological response to cancer that can be used to find gastric cancer patients at an early and putatively curative stage of the disease.
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23
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Wu CH, Lin SR, Yu FJ, Wu DC, Pan YS, Hsieh JS, Huang SY, Wang JY. Development of a high-throughput membrane-array method for molecular diagnosis of circulating tumor cells in patients with gastric cancers. Int J Cancer 2006; 119:373-379. [PMID: 16477642 DOI: 10.1002/ijc.21856] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Recently several noninvasive methods have been employed to detect circulating tumor cells (CTCs) in cancer patients. In this study, we have developed a highly sensitive, high-throughput colorimetric membrane-array method that was designed to detect a panel of mRNA markers including human telomerase reverse transcriptase (hTERT), cytrokeratin-19 (CK-19), carcinoembryonic antigen (CEA) and mucin 1 (MUC1) mRNA for the presence of CTCs in the peripheral blood of patients with gastric cancer (GC). Digoxigenin-labeled cDNA targets synthesized following total RNA isolation from peripheral blood samples of 64 GC patients and 80 healthy individuals were subjected to membrane-array hybridization. The results showed that membrane array could positively detect 5 cancer cells/ml of peripheral blood in GC cell-dilution experiments. The sensitivity, specificity and diagnostic accuracy for hTERT, CK-19, CEA and MUC1 mRNA ranged from 78.1% to 82.8%, 76.3% to 85% and 81.3% to 83.3%, respectively. Both CEA and MUC1 mRNA expression was correlated significantly with all malignant biological properties of GC, such as macroscopic type, depth of tumor invasion, lymph-node metastasis, TNM stage and coexisting distant metastasis (all p < 0.05). Using these 4 markers in combination, the sensitivity, specificity and diagnostic accuracy of membrane array were raised to 89.1%, 91.3% and 90.3%, respectively. The expression of all 4 mRNA markers was an independent predictor for postoperative recurrence/metastasis. GC patients with the expression of all the 4 mRNA markers showed a poorer survival rate than those without the expression of any 1 mRNA marker (p = 0.0223). These findings demonstrated that our membrane-array method could detect CTCs in the circulation of GC patients with considerably high sensitivity and specificity. The identification of CTCs in the peripheral blood may be useful in the auxiliary cancer diagnostics or postoperative surveillance of GC patients for recurrence/metastasis.
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Affiliation(s)
- Chan-Hang Wu
- MedicoGenomic Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
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24
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Abstract
The upper gastrointestinal (GI) cancers have various carcinogenic pathways and precursor lesions, such as dysplasia for esophageal squamous cell carcinoma, Barrett esophagus for esophageal adenocarcinoma, and intestinal metaplasia for the intestinal-type of gastric cancer. Recently, many epigenetic events in carcinogenic pathways have been revealed, along with genomic and genetic alterations. This information has provided deeper insight into an understanding of the mechanisms of upper GI carcinogenesis. Moreover, detection methods of aberrant methylation have been applied to clinical fields to stratify high-risk groups, detect early cancer, and to predict clinical outcomes. In this review, a variety of information is summarized regarding gene hypermethylation in esophageal and gastric cancer.
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Affiliation(s)
- Fumiaki Sato
- Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
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25
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Leung WK, To KF, Chu ESH, Chan MWY, Bai AHC, Ng EKW, Chan FKL, Sung JJY. Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Br J Cancer 2005; 92:2190-4. [PMID: 15942635 PMCID: PMC2361805 DOI: 10.1038/sj.bjc.6602636] [Citation(s) in RCA: 80] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
While there is no reliable serum biomarker for the diagnosis and monitoring of patients with gastric cancer, we tested the potential diagnostic and prognostic values of detecting methylation changes in the serum of gastric cancer patients. DNA was extracted from the pretherapeutic serum of 60 patients with confirmed gastric adenocarcinoma and 22 age-matched noncancer controls. Promoter hypermethylation in 10 tumour-related genes (APC, E-cadherin, GSTP1, hMLH1, MGMT, p15, p16, SOCS1, TIMP3 and TGF-beta RII) was determined by quantitative methylation-specific PCR (MethyLight). Preferential methylation in the serum DNA of gastric cancer patients was noted in APC (17%), E-cadherin (13%), hMLH1 (41%) and TIMP3 (17%) genes. Moreover, patients with stages III/IV diseases tended to have higher concentrations of methylated APC (P=0.08), TIMP3 (P=0.005) and hMLH1 (P=0.03) in the serum. In all, 33 cancers (55%) had methylation detected in the serum in at least one of these four markers, while three normal subjects had methylation detected in the serum (specificity 86%). The combined use of APC and E-cadherin methylation markers identified a subgroup of cancer patients with worse prognosis (median survival 3.3 vs 16.1 months, P=0.006). These results suggest that the detection of DNA methylation in the serum may carry both diagnostic and therapeutic values in gastric cancer patients.
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Affiliation(s)
- W K Leung
- Department of Medicine & Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Sing Street, Shatin, Hong Kong.
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Yang L, Zhu HY, Cheng ZH, Lu R, Chen YX, Fang JY. Expression and methylation of tumor-associated genes in human gastric cancer cell lines. Shijie Huaren Xiaohua Zazhi 2005; 13:1493-1498. [DOI: 10.11569/wcjd.v13.i13.1493] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the expression and methylation of tumor suppressor genes and oncogenes in the carcinogenesis of gastric cancer, and to further explore new methods for the treatment of gastric cancer.
METHODS: The gastric cancer MKN-45 and HGC-27 cell lines were cultured and then exposed to different concentrations (2 μmol/L, 5 μmol/L and 10 μmol/L) of 5-aza-2'-deoxycytidine (5-aza-dC) for 24 and 72 h. MTT assay was used to examine the viability of the cells. Then the DNA and RNA of the cells were extracted and the expression of p16INK4A, p21WAF1, p53, c-myc, and c-Ha-ras were detected by reverse transcription polymerase chain reaction (RT-PCR). At the same time, the cell cycles of MKN-45 and HGC-27 were observed by flow cytometry. Bisulfite modification and sequencing and methylation-specific PCR were used to detect the methylation of p16INK4A and c-myc promoter region.
RESULTS: The concentrations and exposed time of 5-aza-dC had no significant effect on the viability of gastric cancer cells. p16INK4A was expressed in both MKN-45 and HGC-27 cells before treatment. After treated with 5-aza-dC, p16INK4A expression was increased in both kinds of the cells, and the 5-aza-dC concentration and exposed time were different between the two kinds of cells when the most markedly increased expression of p16INK4A appeared. p53, p21WAF1, c-myc and c-Ha-ras were all expressed before and after treatment. HGC-27 cells were blocked at G1 period, but no changes of MKN-45 cell cycle were observed. Methylation in p16INK4A promoter region occurred so that the expression of this gene was reduced. After treated with demethylation agent 5-aza-dC, the expression of p16INK4A was increased.
CONCLUSION: Methylation regulates the expression of p16INK4A, but not p21WAF1, p53, c-myc, and c-Ha-ras. 5-aza-dC can up-regulate the transcription of tumor suppressor gene through demethylation, in which its concentration and exposed time play an important role.
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Abstract
Epigenetic abnormalities, such as aberrant methylation of CpG islands, are inherited over cell divisions, and play important roles in carcinogenesis. Aberrant methylation of CpG islands specific to tumor cells can be used as a marker to detect cancer cells or cancer-derived DNA, taking advantage of the high sensitivity of methods to detect aberrant methylation. Methylations of specific genes or methylation patterns of groups of genes were found to be associated with responses to chemotherapeutics and prognosis. Methylation in non-cancerous tissues is now attracting attention as a tumor risk marker, and is emerging as a target for cancer prevention. Epigenetic alterations are potentially reversible. The use of DNA demethylating agents has turned out to be effective for hematological malignancies, and is being tested in solid tumors. Histone deacetylase inhibitors and methods for gene-specific epigenetic modification are being developed. Application of epigenetics to cancer diagnostics and therapeutics, and possibly to cancer prevention, is coming into clinics.
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Affiliation(s)
- Kazuaki Miyamoto
- Carcinogenesis Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045 Japan
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