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Zheng Y, Xing W, BingWei, Liu X, Liang G, Yuan D, Yang K, Wang W, Chen D, Ma J. Detection of a novel DNA methylation marker panel for esophageal cancer diagnosis using circulating tumor DNA. BMC Cancer 2024; 24:1578. [PMID: 39725880 DOI: 10.1186/s12885-024-13301-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 12/05/2024] [Indexed: 12/28/2024] Open
Abstract
BACKGROUND Esophageal cancer (ECa) is one of the most deadly cancers, with increasing incidence worldwide and poor prognosis. While endoscopy is recommended for the detection of ECa in high-risk individuals, it is not suitable for large-scale screening due to its invasiveness and inconvenience. METHODS In this study, a novel gene methylation panel was developed for a blood-based test, and its diagnostic efficacy was evaluated using a cohort of 304 participants (203 cases, 101 controls). The assessment focused on the DNA methylation levels of SEPTIN9, tissue factor pathway inhibitor 2 (TFPI2), and the fragile histidine triad gene (FHIT) in patients with ECa, benign esophageal disease, and healthy controls. The receiver operating characteristic (ROC) curve was generated for the panel to calculate the area under the curve (AUC), sensitivity, specificity, and 95% confidence intervals (CIs), along with a comparison to the gold standard of pathological examination. The consistency between biomarker and pathological diagnosis was evaluated with kappa analysis conducted with IBM SPSS Statistics. The Chi-square test or Fisher's exact test was utilized to assess the association of test positivity with demographic characteristics. RESULTS In patients with ECa, SEPTIN9, TFPI2, and FHIT DNA methylation levels were significantly higher compared to those with benign esophageal disease or healthy controls. The panel demonstrated promising potential as a noninvasive tool for distinguishing malignant tumors from both healthy controls and benign esophageal diseases, achieving an area under the ROC curve of 0.925 (95% CI: 0.889-0.952), with a sensitivity of 79.8% [95% CI 73.6-85.1%] and specificity of 95.0% [95% CI 88.8-98.4%]. In particular, the panel showed exceptional diagnostic efficiency for stage 0, I, and II cancer patients with sensitivity at 69.0, 75.5%, and 78.9%, respectively. The comparison revealed a Kappa value of 0.725 between RT-PCR testing and the established gold standard of pathological examination, indicating a high level of consistency. Additionally, there was no bias in diagnostic efficiency based on age, gender, or the presence of other malignancies (non-esophageal cancers). CONCLUSIONS The study's findings suggested that the DNA methylation biomarkers panel holds promise as a non-invasive and convenient diagnostic test for ECa. The panel's ability to distinguish malignant tumors from benign esophageal diseases, coupled with its high sensitivity and specificity, presented opportunities to enhance the over-all diagnosis of high-risk population when in conjunction with existing detection methods.
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Affiliation(s)
- Yan Zheng
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Wenqun Xing
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - BingWei
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, 450008, Henan, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, China
| | - Xianben Liu
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Guanghui Liang
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Dongfeng Yuan
- Department of Thoracic Surgery, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Ke Yang
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, 450008, Henan, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, China
| | - Weizhen Wang
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, 450008, Henan, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, China
| | - Dongxu Chen
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, 450008, Henan, China
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, China
| | - Jie Ma
- Department of Molecular Pathology, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, No 127, Dongming Road, Zhengzhou, 450008, Henan, China.
- Henan Key Laboratory of Molecular Pathology, Zhengzhou, Henan, China.
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Bhattacharya A. Epigenetic modifications and regulations in gastrointestinal diseases. EPIGENETICS IN ORGAN SPECIFIC DISORDERS 2023:497-543. [DOI: 10.1016/b978-0-12-823931-5.00005-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Chen Z, Liu X, Liu F, Zhang G, Tu H, Lin W, Lin H. Identification of 4-methylation driven genes based prognostic signature in thyroid cancer: an integrative analysis based on the methylmix algorithm. Aging (Albany NY) 2021; 13:20164-20178. [PMID: 34456184 PMCID: PMC8436924 DOI: 10.18632/aging.203338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 07/01/2021] [Indexed: 12/09/2022]
Abstract
Thyroid cancer (TC) is known with a high rate of persistence and recurrence. We aimed to develop a prognostic signature to monitor and assess the survival of TC patients. mRNA expression and methylation data were downloaded from the TCGA database. Then, R package methylmix was applied to construct a mixed model was used to identify methylation-driven genes (MDGs) according to the methylation levels. Furthermore, an MDGs based prognostic signature and predictive nomogram were constructed according to the analysis of univariate and multivariate Cox regression. Totally 62 methylation-driven genes that were mainly enriched in substrate-dependent cell migration, cellular response to mechanical stimulus, et al. were found in TC tissues. aldolase C (AldoC), C14orf62, dishevelled 1 (DVL1), and protein tyrosine phosphatase receptor type C (PTPRC) were identified to be significantly related to patients' survival, and may serve as independent prognostic biomarkers for TC. Additionally, the prognostic methylation signature and a novel prognostic, predictive nomogram was established based on the methylation level of 4 MDGs. In this study, we developed a 4-MDGs based prognostic model, which might be the potential predictors for the survival rate of TC patients, and this findings might provide a novel sight for accurate monitoring and prognosis assessment.
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Affiliation(s)
- Zhiwei Chen
- Department of Pathology, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Xiaoli Liu
- Department of Pathology, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Fangfang Liu
- Department of Pathology, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Guolie Zhang
- Department of Thyroid Surgery, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Haijian Tu
- Clinical Laboratory, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Wei Lin
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
| | - Haifeng Lin
- Department of Gastroenterology, The Affiliated Hospital of Putian University, Putian 351100, Fujian Province, China
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Businello G, Parente P, Mastracci L, Pennelli G, Traverso G, Milione M, Bellan E, Michelotto M, Kotsafti A, Grillo F, Fassan M. The Pathologic and Molecular Landscape of Esophageal Squamous Cell Carcinogenesis. Cancers (Basel) 2020; 12:2160. [PMID: 32759723 PMCID: PMC7465394 DOI: 10.3390/cancers12082160] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 07/27/2020] [Accepted: 08/01/2020] [Indexed: 02/07/2023] Open
Abstract
Esophageal squamous cell carcinoma represents the most common histotype of epithelial neoplasm occurring within esophageal mucosa worldwide. Despite the comprehensive molecular characterization of this entity, to date no significant targeted therapy has been introduced into clinical practice. In this review, we describe the molecular landscape of esophageal squamous cell carcinoma based on the most recent literature. Moreover, we focus on other rare variants and on the relationship with head and neck squamous cell carcinomas.
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Affiliation(s)
- Gianluca Businello
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (G.P.); (E.B.); (M.M.)
| | - Paola Parente
- Pathology Unit, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, 71013 San Giovanni Rotondo FG, Italy;
| | - Luca Mastracci
- Anatomic Pathology, Ospedale Policlinico San Martino IRCCS, 16132 Genova, Italy; (L.M.); (F.G.)
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, 16132 Genova, Italy;
| | - Gianmaria Pennelli
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (G.P.); (E.B.); (M.M.)
| | | | - Massimo Milione
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, 16132 Genova, Italy;
| | - Elena Bellan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (G.P.); (E.B.); (M.M.)
| | - Mauro Michelotto
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (G.P.); (E.B.); (M.M.)
| | - Andromachi Kotsafti
- Laboratory of Advanced Translational Research, Veneto Institute of Oncology IOV–IRCCS, 35128 Padua, Italy;
| | - Federica Grillo
- Anatomic Pathology, Ospedale Policlinico San Martino IRCCS, 16132 Genova, Italy; (L.M.); (F.G.)
- Anatomic Pathology, Department of Surgical Sciences and Integrated Diagnostics (DISC), University of Genova, 16132 Genova, Italy;
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua, 35121 Padua, Italy; (G.B.); (G.P.); (E.B.); (M.M.)
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Lv L, Cao L, Hu G, Shen Q, Wu J. Methylation-Driven Genes Identified as Novel Prognostic Indicators for Thyroid Carcinoma. Front Genet 2020; 11:294. [PMID: 32296463 PMCID: PMC7136565 DOI: 10.3389/fgene.2020.00294] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 03/12/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Aberrant DNA methylation plays an crucial role in tumorigenesis through regulating gene expression. Nevertheless, the exact role of methylation in the carcinogenesis of thyroid cancer and its association with prognosis remains unclear. The purpose of this study is to explore the DNA methylation-driven genes in thyroid cancer by integrative bioinformatics analysis. METHODS The transcriptome profiling data and DNA methylation data of thyroid cancer were downloaded from The Cancer Genome Atlas (TCGA) database. The methylmix R package was used to screen DNA methylation-driven genes in thyroid cancer. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were conducted to annotate the function of methylation-driven genes. Univariate Cox regression analyses was performed to distinguish prognosis-related methylation-driven genes. Multivariate Cox regression analyses was utilized to build a prognostic multi-gene signature. A survival analysis was carried out to determine the individual prognostic significance of this multi-gene signature. RESULTS A total of 51 methylation-driven genes were identified. The functional analysis indicated that these genes were significantly enriched in diverse biological processes (BP) and pathways related to the malignancy processes. Four of these genes (RDH5, TREM1, BIRC7, and SLC26A7) were selected to construct the risk evaluation model. Patients in the low-risk group had an conspicuously better overall survival (OS) than those in high-risk group (p < 0.001). The area under the receiver operating characteristic (ROC) curve for this model was 0.836, suggesting a good specificity and sensitivity. Subsequent survival analysis revealed that this four-gene signature served as an independent indicator for the prognosis of thyroid cancer. Moreover, the prognostic signature was well validated in a external thyroid cancer cohort. CONCLUSION We identified methylation-driven genes in thyroid cancer with independent prognostic value, which may offer new insight into molecular mechanisms of thyroid cancer and provide new possibility for individualized treatment of thyroid cancer patients.
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Affiliation(s)
- Liting Lv
- Department of Thyroid and Breast Surgery, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, China
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Lu T, Chen D, Wang Y, Sun X, Li S, Miao S, Wo Y, Dong Y, Leng X, Du W, Jiao W. Identification of DNA methylation-driven genes in esophageal squamous cell carcinoma: a study based on The Cancer Genome Atlas. Cancer Cell Int 2019; 19:52. [PMID: 30886542 PMCID: PMC6404309 DOI: 10.1186/s12935-019-0770-9] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2018] [Accepted: 02/28/2019] [Indexed: 02/06/2023] Open
Abstract
Background Aberrant DNA methylations are significantly associated with esophageal squamous cell carcinoma (ESCC). In this study, we aimed to investigate the DNA methylation-driven genes in ESCC by integrative bioinformatics analysis. Methods Data of DNA methylation and transcriptome profiling were downloaded from TCGA database. DNA methylation-driven genes were obtained by methylmix R package. David database and ConsensusPathDB were used to perform gene ontology (GO) analysis and pathway analysis, respectively. Survival R package was used to analyze overall survival analysis of methylation-driven genes. Results Totally 26 DNA methylation-driven genes were identified by the methylmix, which were enriched in molecular function of DNA binding and transcription factor activity. Then, ABCD1, SLC5A10, SPIN3, ZNF69, and ZNF608 were recognized as significant independent prognostic biomarkers from 26 methylation-driven genes. Additionally, a further integrative survival analysis, which combined methylation and gene expression data, was identified that ABCD1, CCDC8, FBXO17 were significantly associated with patients’ survival. Also, multiple aberrant methylation sites were found to be correlated with gene expression. Conclusion In summary, we studied the DNA methylation-driven genes in ESCC by bioinformatics analysis, offering better understand of molecular mechanisms of ESCC and providing potential biomarkers precision treatment and prognosis detection. Electronic supplementary material The online version of this article (10.1186/s12935-019-0770-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Tong Lu
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Di Chen
- 2Department of Gastroenterology, Affiliated Hospital of Qingdao University, No 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Yuanyong Wang
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Xiao Sun
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Shicheng Li
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Shuncheng Miao
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Yang Wo
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Yanting Dong
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Xiaoliang Leng
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Wenxing Du
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
| | - Wenjie Jiao
- 1Department of Thoracic Surgery, Affiliated Hospital of Qingdao University, No. 16 Jiangsu Road, Shinan District, Qingdao, 266003 China
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Dong Y, Yi X, Yujie Z, Huixia Z, Yan C. Relationship between the Methylation of Folic Acid Metabolism-Related Genes and the Incidence and Prognosis of Esophageal Cancer among Ethnic Kazakhs. J Cancer 2018; 9:2865-2875. [PMID: 30123355 PMCID: PMC6096358 DOI: 10.7150/jca.25270] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 05/30/2018] [Indexed: 01/24/2023] Open
Abstract
Objective: To investigate the relationship between the hypermethylation of folic acid metabolism-related genes and the incidence and prognosis of esophageal cancer among ethnic Kazakhs in Xinjiang (China). Methods: According to the standard of esophageal cancer diagnosis, exclusion and epidemiological investigation of the experimental and control groups. Ion capture immunoassays were used to measure serum folic acid levels, while methylation-specific polymerase chain reaction was used to detect gene promoter methylation levels. Log-rank tests and Cox regression models were used to identify prognostic factors in the patient population. Results: Serum folic acid levels in the experimental (cancer) group were significantly lower than in the control (non-cancer) group (Z = -9.13, P < 0.001). Furthermore, the methylation rates of MTHFR, CBS, MGMT, P16, FHIT, and RASSF1A in the experimental group were significantly higher than in the control group. Multivariate analysis identified depth of tumor invasion, regional lymph node metastasis, tumor-node-metastasis stage, and CBS and RASSF1A gene methylation status as independent prognostic factors; female gender and high serum folic acid levels were favorable prognostic factors. Conclusions: Low serum folic acid level is a risk factor for esophageal cancer among ethic Kazakhs. Moreover, methylation of MTHFR, CBS, MGMT, P16, FHIT, and RASSF1A is closely related to esophageal cancer tumorigenesis.
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Affiliation(s)
- Yin Dong
- The First Affiliated Hospital of Jiaxing University, Jiaxing, China.,Tumor Affiliated Hospital of Xinjiang Medical University, Urumqi, China
| | - Xu Yi
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
| | - Zhen Yujie
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
| | - Zhang Huixia
- Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, China
| | - Chen Yan
- The Medical School of Jiaxing University, Jiaxing, China.,Department of Health Toxicology, College of Public Health, Xinjiang Medical University, Urumqi, 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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Zeng R, Liu Y, Jiang ZJ, Huang JP, Wang Y, Li XF, Xiong WB, Wu XC, Zhang JR, Wang QE, Zheng YF. EPB41L3 is a potential tumor suppressor gene and prognostic indicator in esophageal squamous cell carcinoma. Int J Oncol 2018; 52:1443-1454. [PMID: 29568917 PMCID: PMC5873871 DOI: 10.3892/ijo.2018.4316] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 02/15/2018] [Indexed: 02/06/2023] Open
Abstract
Although there have been reports about the role of erythrocyte membrane protein band 4.1 like 3 (EPB41L3) in several types of cancer, primarily in non-small-cell lung carcinoma, the molecular function and modulatory mechanisms of EPB41L3 remain unclear. In specific, the functional and clinical significance of EPB41L3 in esophageal squamous cell carcinoma (ESCC) has not been explored to date. In the present study, reduced EPB41L3 expression was demonstrated in ESCC cell lines and tissues, which was due to its high methylation rate. Ectopic expression of EPB41L3 in ESCC cells inhibited cell proliferation in vivo and in vitro. In addition, EPB41L3 overexpression induced apoptosis and G2/M cell cycle arrest by activating Caspase-3/8/9 and Cyclin-dependent kinase 1/Cyclin B1 signaling, respectively. Notably, patients with higher EPB41L3 expression had markedly higher overall survival rates compared with patients with lower EPB41L3 expression. In summary, the present results suggest that EPB41L3 may be a tumor suppressor gene in ESCC development, representing a potential therapeutic target and a prognostic indicator for ESCC.
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Affiliation(s)
- Rong Zeng
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Yi Liu
- Department of Neurosurgery, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Zhao-Jing Jiang
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Jun-Peng Huang
- Department of Medical Oncology, Fujian Provincial Hospital, Fuzhou, Fujian 350001, P.R. China
| | - Yu Wang
- Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Xu-Feng Li
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Wei-Bin Xiong
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Xiao-Cong Wu
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Ji-Ren Zhang
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Qi-En Wang
- Department of Radiology, Division of Radiobiology, Ohio State University Wexner Medical Center, Columbus, OH 43210, USA
| | - Yan-Fang Zheng
- Oncology Center, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
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Modhukur V, Iljasenko T, Metsalu T, Lokk K, Laisk-Podar T, Vilo J. MethSurv: a web tool to perform multivariable survival analysis using DNA methylation data. Epigenomics 2018; 10:277-288. [DOI: 10.2217/epi-2017-0118] [Citation(s) in RCA: 198] [Impact Index Per Article: 28.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aim: To develop a web tool for survival analysis based on CpG methylation patterns. Materials & methods: We utilized methylome data from ‘The Cancer Genome Atlas’ and used the Cox proportional-hazards model to develop an interactive web interface for survival analysis. Results: MethSurv enables survival analysis for a CpG located in or around the proximity of a query gene. For further mining, cluster analysis for a query gene to associate methylation patterns with clinical characteristics and browsing of top biomarkers for each cancer type are provided. MethSurv includes 7358 methylomes from 25 different human cancers. Conclusion: The MethSurv tool is a valuable platform for the researchers without programming skills to perform the initial assessment of methylation-based cancer biomarkers.
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Affiliation(s)
| | - Tatjana Iljasenko
- Institute of Computer Science, University of Tartu, 50409 Tartu, Estonia
| | - Tauno Metsalu
- Institute of Computer Science, University of Tartu, 50409 Tartu, Estonia
| | - Kaie Lokk
- United Laboratories of Tartu University Hospital, Tartu University Hospital, 50406 Tartu, Estonia
| | - Triin Laisk-Podar
- Competence Centre on Health Technologies, 50410 Tartu, Estonia
- Women's Clinic, Institute of Clinical Medicine, University of Tartu, 50406 Tartu, Estonia
| | - Jaak Vilo
- Institute of Computer Science, University of Tartu, 50409 Tartu, Estonia
- Health Data Analytics, Software Technologies & Applications Competence Center STACC, Ülikooli 2, 51003 Tartu, Estonia
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11
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Gao D, Herman JG, Guo M. The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer. Oncotarget 2018; 7:37331-37346. [PMID: 26967246 PMCID: PMC5095080 DOI: 10.18632/oncotarget.7949] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/20/2016] [Indexed: 12/22/2022] Open
Abstract
The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system. Unrepaired DNA damage is a major source of potentially mutagenic lesions that drive carcinogenesis. In addition to gene mutation, DNA methylation occurs more frequently in DDR genes in human cancer. Thus, DNA methylation may play more important roles in DNA damage repair genes to drive carcinogenesis. Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer. MGMT methylation is a marker for poor prognosis in human glioma, while, MGMT methylation is a sensitive marker of glioma cells to alkylating agents. Aberrant epigenetic changes in DNA damage repair genes may serve as therapeutic targets. Treatment of MLH1-methylated colon cancer cell lines with the demethylating agent 5′-aza-2′-deoxycytidine induces the expression of MLH1 and sensitizes cancer cells to 5-fluorouracil. Synthetic lethality is a more exciting approach in patients with DDR defects. PARP inhibitors are the most effective anticancer reagents in BRCA-deficient cancer cells.
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Affiliation(s)
- Dan Gao
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.,Medical College of NanKai University, Tianjin, China
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Mingzhou Guo
- Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China
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Lin DC, Wang MR, Koeffler HP. Genomic and Epigenomic Aberrations in Esophageal Squamous Cell Carcinoma and Implications for Patients. Gastroenterology 2018; 154:374-389. [PMID: 28757263 PMCID: PMC5951382 DOI: 10.1053/j.gastro.2017.06.066] [Citation(s) in RCA: 172] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 06/05/2017] [Accepted: 06/07/2017] [Indexed: 12/28/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common malignancy without effective therapy. The exomes of more than 600 ESCCs have been sequenced in the past 4 years, and numerous key aberrations have been identified. Recently, researchers reported both inter- and intratumor heterogeneity. Although these are interesting observations, their clinical implications are unclear due to the limited number of samples profiled. Epigenomic alterations, such as changes in DNA methylation, histone acetylation, and RNA editing, also have been observed in ESCCs. However, it is not clear what proportion of ESCC cells carry these epigenomic aberrations or how they contribute to tumor development. We review the genomic and epigenomic characteristics of ESCCs, with a focus on emerging themes. We discuss their clinical implications and future research directions.
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Affiliation(s)
- De-Chen Lin
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
| | - Ming-Rong Wang
- State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - H Phillip Koeffler
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California; Cancer Science Institute of Singapore, National University of Singapore, Singapore; National University Cancer Institute, National University Hospital Singapore, Singapore
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13
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Yamamoto S, Yashima K, Kawata S, Hosoda K, Tamoto A, Ikebuchi Y, Matsumoto K, Kawaguchi K, Harada K, Murawaki Y, Isomoto H. Frequent aberrant p53 and Fhit expression in endoscopically resected superficial hypopharyngeal cancer and esophageal cancer. Oncol Lett 2017; 14:587-592. [PMID: 28693209 PMCID: PMC5494673 DOI: 10.3892/ol.2017.6271] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2015] [Accepted: 02/17/2017] [Indexed: 01/29/2023] Open
Abstract
In the last decade, the incidence rate of detection rate of superficial head, neck and esophageal squamous cell carcinomas has increased with the development of endoscopic imaging techniques. These cancers are thought to arise independently subsequent to tissue exposure to a common carcinogen e.g. alcohol or tobacco. This phenomenon has been termed field cancerization. To determine the molecular background of the development of hypopharyngeal squamous cell carcinomas (HPSCCs) and double esophageal squamous cell carcinomas (DESCCs), the present study immunohistochemically assessed tumor-related protein expression [p53, Fhit (fragile histidine triad), E-cadherin and activation-induced cytidine deaminase (AID)], and subsequently determined the correlation between protein expression and clinicopathological data. Tumor specimens of 9 HPSCCs and 9 DESCCs were endoscopically obtained from 8 patients with HPSCC. The 9 DESCCs, including 5 synchronous and 4 metachronous lesions, were all obtained from four patients with HPSCC. The overexpression of p53 and loss of Fhit expression was immunohistochemically detected in 8 (88.9%) and 8 (88.9%) of the 9 HPSCCs and in 8 (88.9%) and 8 (88.9%) of the 9 DESCCs, respectively, which demonstrated the high frequency of such expression. Additionally, 7 out of 9 HPSCCs, and 7 out of 9 DESCCs demonstrated aberrant expression of p53 and Fhit. The rate of aberrant AID and E-cadherin expression was 67 and 44% in HPSCCs and 44 and 44% in DESCC, respectively. These results suggested that aberrant p53 and Fhit expression was involved in the development of HPSCC and their DESCC, and that their expression may be used for the prediction of DESCC development in patients with HPSCC, thereby acting as a biomarker of field cancerization.
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Affiliation(s)
- Sohei Yamamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Soichiro Kawata
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Kohei Hosoda
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Akihiro Tamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Kazuya Matsumoto
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Yoshikazu Murawaki
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Faculty of Medicine, University of Tottori, Yonago 683-8504, Japan
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14
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Zhao Y, Min L, Xu C, Shao L, Guo S, Cheng R, Xing J, Zhu S, Zhang S. Construction of disease-specific transcriptional regulatory networks identifies co-activation of four gene in esophageal squamous cell carcinoma. Oncol Rep 2017; 38:411-417. [PMID: 28560409 DOI: 10.3892/or.2017.5681] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 02/02/2017] [Indexed: 11/06/2022] Open
Abstract
Even though various molecules may serve as biomarkers, little is known concerning the mechanisms underlying the carcinogenesis of ESCC, particularly the transcriptional regulatory network. Thus, in the present study, paired ESCC and non-cancerous (NC) tissues were assayed by Affymetrix microarray assays. Passing Attributes between Networks for Data Assimilation (PANDA) was used to construct networks between transcription factors (TFs) and their targets. AnaPANDA program was applied to compare the regulatory networks. A hypergeometric distribution model-based target profile similarity analysis was utilized to find co-activation effects using both TF-target networks and differential expression data. There were 1,116 genes upregulated and 1,301 genes downregulated in ESCC compared with NC tissues. In TF-target networks, 16,970 ESCC-specific edges and 9,307 NC-specific edges were identified. Edge enrichment analysis by AnaPANDA indicated 17 transcription factors (NFE2L2, ELK4, PAX6, TLX1, ESR1, ZNF143, TP53, REL, ELF5, STAT1, TBP, NHLH1, FOXL1, SOX9, STAT3, ELK1, and HOXA5) suppressed in ESCC and 5 (SPIB, BRCA1, MZF1, MAFG and NFE2L1) activated in ESCC. For SPIB, MZF1, MAFG and NFE2L1, a strong and significant co-activation effect among them was detected in ESCC. In conclusion, the construction of transcriptional regulatory networks found SPIB, MZF1, MAFG and NFE2L1 co-activated in ESCC, which provides distinctive insight into the carcinogenesis mechanism of ESCC.
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Affiliation(s)
- Yu Zhao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Li Min
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Changqin Xu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Linlin Shao
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Shuilong Guo
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Rui Cheng
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Jie Xing
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Shengtao Zhu
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
| | - Shutian Zhang
- Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesions of Digestive Disease, Xicheng, Beijing 100050, P.R. China
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15
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Hosoda K, Yashima K, Tamoto A, Yamamoto S, Kawata S, Ikebuchi Y, Matsumoto K, Kawaguchi K, Harada K, Murawaki Y, Isomoto H. Expression of methylation-modulated tumor-related genes in endoscopically resected early esophageal squamous neoplasia. Oncol Lett 2017; 14:737-742. [PMID: 28693228 PMCID: PMC5494775 DOI: 10.3892/ol.2017.6196] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2016] [Accepted: 03/28/2017] [Indexed: 02/06/2023] Open
Abstract
Smoking and alcohol consumption are major risk factors for the development of esophageal squamous cell carcinoma (ESCC). Recent studies have demonstrated that smoking and alcohol consumption may be associated with altered DNA methylation in human cancer development. The aim of the present study was to evaluate methylation-modulated protein expression of tumor-related genes (TRGs) in the early stages of esophageal squamous neoplasia (ESN). ESN tissue samples (n=141) comprising 19 cases of low-grade intraepithelial neoplasia (LGIN), 70 of high-grade intraepithelial neoplasia/carcinoma in situ (HGIN/CIS) and 52 of invasive cancer, were endoscopically resected. The methylation-modulated protein expression of 5 TRGs [fragile histidine triad (FHIT), E-cadherin, MutL homolog 1 (MLH1) /MutS homolog 2 (MSH2) and cyclooxygenase-2 (COX-2)] as well as p53 was examined with immunohistochemistry, and their expression was compared with patient clinicopathological characteristics. Reduced or loss of FHIT, E-cadherin, MLH1/MSH2 and COX-2 expression was detected in 26.3 (5/19), 5.3 (1/19), 0 (0/19) and 63.2% (12/19) of LGIN cases, 61.4 (43/70), 18.6 (13/70), 7.1 (5/70) and 65.7% (46/70) of HGIN/CIS cases, and 78.8 (41/52), 50.0 (26/52), 11.5 (6/52) and 59.6% (31/52) of invasive cancer cases, respectively. Reduced or absent expression of FHIT and E-cadherin was significantly associated with neoplastic progression (FHIT, P=0.0007; E-cadherin, P=0.00014). The mean number of TRGs (FHIT, E-cadherin, MLH1/MSH2, and COX-2) that exhibited reduced or absent expression in LGIN, HGIN/CIS and invasive cancer specimens was 1.12±0.61, 1.66±0.93 and 2.09±0.96, respectively, demonstrating a significant stepwise increment from LGIN to HGIN/CIS and then to invasive cancer (P<0.05). p53 overexpression was frequently detected in ESN with head and neck carcinomas. However p53 overexpression was not significantly associated with ESN progression. An increase in the number of the 5 TRG proteins with reduced or loss of expression in the early stages of esophageal tumorigenesis was demonstrated, and their decreased expression was observed to be associated with tumor progression. Therefore, smoking and alcohol drinking may be associated with not only carcinogenesis but also the progression of ESN.
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Affiliation(s)
- Kohei Hosoda
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Kazuo Yashima
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Akihiro Tamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Sohei Yamamoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Soichiro Kawata
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Yuichiro Ikebuchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Kazuya Matsumoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Koichiro Kawaguchi
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Kenichi Harada
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Yoshikazu Murawaki
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Hajime Isomoto
- Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
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Chen X, Hu H, Liu J, Yang Y, Liu G, Ying X, Chen Y, Li B, Ye C, Wu D, Duan S. FOXF2 promoter methylation is associated with prognosis in esophageal squamous cell carcinoma. Tumour Biol 2017; 39:1010428317692230. [PMID: 28222662 DOI: 10.1177/1010428317692230] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Esophageal squamous cell carcinoma is a commonly malignant tumor of digestive tract with poor prognosis. Previous studies suggested that forkhead box F2 ( FOXF2) could be a candidate gene for assessing and predicting the prognosis of human cancers. However, the relationship between FOXF2 promoter methylation and the prognosis of esophageal squamous cell carcinoma remained unclear. Formalin-fixed, paraffin-embedded esophageal squamous cell carcinoma tissues of 135 esophageal squamous cell carcinoma patients were detected for FOXF2 promoter methylation status by methylation-specific polymerase chain reaction approach. DNA methylation results were evaluated with regard to clinicopathological features and overall survival. Our study confirmed that FOXF2 promoter hypermethylation could independently predict a poorer overall survival of esophageal squamous cell carcinoma patients ( p = 0.002), which was consistent with the data mining results of the data from 82 esophageal squamous cell carcinoma patients in The Cancer Genome Atlas datasets ( p = 0.036). In addition, no correlation was found between FOXF2 promoter methylation and other clinic pathological parameters (age, gender, differentiation, lymph node metastasis, stage, cutting edge, vascular invasion, smoking behavior, and drinking history). In conclusion, FOXF2 methylation might be a useful prognostic biomarker for esophageal squamous cell carcinoma patients.
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Affiliation(s)
- Xiaoying Chen
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Haochang Hu
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Jing Liu
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Yong Yang
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Guili Liu
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Xiuru Ying
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Yingmin Chen
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Bin Li
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Cong Ye
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
| | - Dongping Wu
- 2 Department of Medical Oncology, Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University), Shaoxing, China
| | - Shiwei Duan
- 1 Medical Genetics Center, School of Medicine, Ningbo University, Ningbo, China
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17
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Hossain T, Mahmudunnabi G, Masud MK, Islam MN, Ooi L, Konstantinov K, Hossain MSA, Martinac B, Alici G, Nguyen NT, Shiddiky MJA. Electrochemical biosensing strategies for DNA methylation analysis. Biosens Bioelectron 2017; 94:63-73. [PMID: 28259051 DOI: 10.1016/j.bios.2017.02.026] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 02/15/2017] [Accepted: 02/16/2017] [Indexed: 12/31/2022]
Abstract
DNA methylation is one of the key epigenetic modifications of DNA that results from the enzymatic addition of a methyl group at the fifth carbon of the cytosine base. It plays a crucial role in cellular development, genomic stability and gene expression. Aberrant DNA methylation is responsible for the pathogenesis of many diseases including cancers. Over the past several decades, many methodologies have been developed to detect DNA methylation. These methodologies range from classical molecular biology and optical approaches, such as bisulfite sequencing, microarrays, quantitative real-time PCR, colorimetry, Raman spectroscopy to the more recent electrochemical approaches. Among these, electrochemical approaches offer sensitive, simple, specific, rapid, and cost-effective analysis of DNA methylation. Additionally, electrochemical methods are highly amenable to miniaturization and possess the potential to be multiplexed. In recent years, several reviews have provided information on the detection strategies of DNA methylation. However, to date, there is no comprehensive evaluation of electrochemical DNA methylation detection strategies. Herein, we address the recent developments of electrochemical DNA methylation detection approaches. Furthermore, we highlight the major technical and biological challenges involved in these strategies and provide suggestions for the future direction of this important field.
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Affiliation(s)
- Tanvir Hossain
- Department of Biochemistry & Molecular Biology, Shahjalal University of Science & Technology, Sylhet 3114, Bangladesh
| | - Golam Mahmudunnabi
- Department of Genetic Engineering and Biotechnology, Shahjalal University of Science & Technology, Sylhet 3114, Bangladesh
| | - Mostafa Kamal Masud
- Department of Biochemistry & Molecular Biology, Shahjalal University of Science & Technology, Sylhet 3114, Bangladesh; Institute for Superconducting and Electronic Materials, Australian Institute for Innovative Materials (AIIM), University of Wollongong, Squires Way, Innovation Campus, North Wollongong, NSW 2519, Australia; Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan, QLD 4111, Australia
| | - Md Nazmul Islam
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan, QLD 4111, Australia; School of Natural Sciences, Griffith University (Nathan Campus), Nathan, QLD 4111, Australia
| | - Lezanne Ooi
- Illawarra Health and Medical Research Institute, School of Biological Sciences, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia
| | - Konstantin Konstantinov
- Institute for Superconducting and Electronic Materials, Australian Institute for Innovative Materials (AIIM), University of Wollongong, Squires Way, Innovation Campus, North Wollongong, NSW 2519, Australia
| | - Md Shahriar Al Hossain
- Institute for Superconducting and Electronic Materials, Australian Institute for Innovative Materials (AIIM), University of Wollongong, Squires Way, Innovation Campus, North Wollongong, NSW 2519, Australia
| | - Boris Martinac
- Victor Chang Cardiac Research Institute, Darlinghurst, NSW 2010, Australia
| | - Gursel Alici
- ARC Centre of Excellence for Electromaterials Science, University of Wollongong, Northfields Avenue, Wollongong, NSW 2522, Australia
| | - Nam-Trung Nguyen
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan, QLD 4111, Australia
| | - Muhammad J A Shiddiky
- Queensland Micro- and Nanotechnology Centre, Griffith University, Nathan, QLD 4111, Australia; School of Natural Sciences, Griffith University (Nathan Campus), Nathan, QLD 4111, Australia.
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Zhu J, Ling Y, Xu Y, Lu M, Liu Y, Zhang C. Promoter hypermethylation of the RECK gene is associated with its low expression and poor survival of esophageal squamous cell carcinoma. Oncol Lett 2017; 13:1911-1918. [PMID: 28454343 DOI: 10.3892/ol.2017.5656] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 10/25/2016] [Indexed: 02/06/2023] Open
Abstract
The present study aimed to investigate the association between the methylation status of the reversion-inducing cysteine-rich protein with kazal motifs (RECK) gene and its mRNA expression levels in patients with esophageal squamous cell carcinoma (ESCC). The methylation status of RECK was analyzed by methylation-specific polymerase chain reaction (PCR), and RECK mRNA expression levels were analyzed by quantitative PCR, in 310 paired ESCC tissues. The mean RECK methylation index (MI) was 0.65 in ESCCs and 0.49 in non-tumor samples. There was a significant association between RECK methylation and the American Joint Committee on Cancer stage and lymph node metastasis in ESCC (P<0.0001; P=0.001). The mRNA expression level of RECK was lower in ESCC tissues (mean-∆Cq=-4.66) compared with non-tumor tissues (mean-∆Cq=-2.79), and decreased RECK mRNA expression levels were associated with lymph node metastasis in ESCC. In addition, RECK mRNA levels were decreased in ESCC patients with hypermethylation of the RECK gene (∆MI >0.16; mean-∆∆Cq=-2.85) compared with those with hypomethylation of the RECK gene (∆MI ≤0.16; mean-∆∆Ct=-0.83), and there was a significant difference in the mRNA expression levels of RECK between those with N0-1 and N2-3 lymph node metastasis (P<0.0001). A significant correlation was observed between RECK mRNA expression levels, the MI of RECK and poor postoperative survival (P=0.0003; P<0.0001). The results of the present study suggested that promoter hypermethylation may be an important factor for loss of RECK mRNA expression and may be an indicator of poor survival in ESCC.
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Affiliation(s)
- Jing Zhu
- Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
| | - Yang Ling
- Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
| | - Yun Xu
- Department of Oncology, Nanyang Center Hospital, Nanyang, Henan 473000, P.R. China
| | - Mingzhu Lu
- Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
| | - Yongping Liu
- Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
| | - Changsong Zhang
- Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou, Jiangsu 213002, P.R. China
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Ma K, Cao B, Guo M. The detective, prognostic, and predictive value of DNA methylation in human esophageal squamous cell carcinoma. Clin Epigenetics 2016; 8:43. [PMID: 27110300 PMCID: PMC4840959 DOI: 10.1186/s13148-016-0210-9] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Accepted: 04/14/2016] [Indexed: 12/17/2022] Open
Abstract
Esophageal cancer is one of the most common malignancies in the world. Squamous cell carcinoma accounts for approximately 90 % of esophageal cancer cases. Genetic and epigenetic changes have been found to accumulate during the development of various cancers, including esophageal squamous carcinoma (ESCC). Tobacco smoking and alcohol consumption are two major risk factors for ESCC, and both tobacco and alcohol were found to induce methylation changes in ESCC. Growing evidence demonstrates that aberrant epigenetic changes play important roles in the multiple-step processes of carcinogenesis and tumor progression. DNA methylation may occur in the key components of cancer-related signaling pathways. Aberrant DNA methylation affects genes involved in cell cycle, DNA damage repair, Wnt, TGF-β, and NF-κB signaling pathways, including P16, MGMT, SFRP2, DACH1, and ZNF382. Certain genes methylated in precursor lesions of the esophagus demonstrate that DNA methylation may serve as esophageal cancer early detection marker, such as methylation of HIN1, TFPI-2, DACH1, and SOX17. CHFR methylation is a late stage event in ESCC and is a sensitive marker for taxanes in human ESCC. FHIT methylation is associated with poor prognosis in ESCC. Aberrant DNA methylation changes may serve as diagnostic, prognostic, and chemo-sensitive markers. Characterization of the DNA methylome in ESCC will help to better understand its mechanisms and develop improved therapies.
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Affiliation(s)
- Kai Ma
- />Department of Thoracic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, China
| | - Baoping Cao
- />Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
| | - Mingzhou Guo
- />Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, #28 Fuxing Road, Beijing, 100853 China
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20
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Wu X, Wu G, Yao X, Hou G, Jiang F. The clinicopathological significance and ethnic difference of FHIT hypermethylation in non-small-cell lung carcinoma: a meta-analysis and literature review. DRUG DESIGN DEVELOPMENT AND THERAPY 2016; 10:699-709. [PMID: 26929601 PMCID: PMC4760666 DOI: 10.2147/dddt.s85253] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Emerging evidence indicates that FHIT is a candidate tumor suppressor in many types of tumors including non-small-cell lung carcinoma (NSCLC). However, the prognostic value and correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. In this report, we performed a meta-analysis to evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics of human NSCLC patients. Final analysis of 1,801 NSCLC patients from 18 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue. The pooled odds ratio (OR) from ten studies included 819 NSCLC and 792 normal lung tissues (OR =7.51, 95% confidence interval [CI] =2.98-18.91, P<0.0001). Subgroup analysis based on ethnicity implied that FHIT hypermethylation level was higher in NSCLC tissues than in normal tissues in both Caucasians (P=0.02) and Asians (P<0.0001), indicating that the difference in Asians was much more significant. FHIT hypermethylation was also correlated with sex status, smoking status, as well as pathological types. In addition, patients with FHIT hypermethylation had a lower survival rate than those without (hazard ratio =1.73, 95% CI =1.10-2.71, P=0.02). The results of this meta-analysis suggest that FHIT hypermethylation is associated with an increased risk and poor survival in NSCLC patients. FHIT hypermethylation, which induces the inactivation of FHIT gene, plays an important role in the carcinogenesis and clinical outcome and may serve as a potential diagnostic marker and drug target of NSCLC.
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Affiliation(s)
- Xiaoyu Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Guannan Wu
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Xuequan Yao
- Department of Surgical Oncology, Affiliated Hospital of Nanjing University of Traditional Chinese Medicine, Nanjing, People's Republic of China
| | - Gang Hou
- Department of Respiratory Medicine, The First Hospital of China Medical University, Shenyang, People's Republic of China
| | - Feng Jiang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, People's Republic of China
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The clinicopathological significance of FHIT hypermethylation in non-small cell lung cancer, a meta-analysis and literature review. Sci Rep 2016; 6:19303. [PMID: 26796853 PMCID: PMC4726317 DOI: 10.1038/srep19303] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 11/18/2015] [Indexed: 12/17/2022] Open
Abstract
Emerging evidence indicates that FHIT is a candidate tumor suppressor in non-small cell lung cancer (NSCLC). However, the correlation between FHIT hypermethylation and clinicopathological characteristics of NSCLC remains unclear. Thus, we conducted a meta-analysis to quantitatively evaluate the effects of FHIT hypermethylation on the incidence of NSCLC and clinicopathological characteristics. Final analysis of 1717 NSCLC patients from 16 eligible studies was performed. FHIT hypermethylation was found to be significantly higher in NSCLC than in normal lung tissue, the pooled OR from 8 studies including 735 NSCLC and 708 normal lung tissue, OR = 5.45, 95% CI = 2.15-13.79, p = 0.0003. FHIT hypermethylation was also correlated with sex status, smoking status, as well as pathological types. We did not find that FHIT hypermethylation was correlated with the differentiated types or clinical stages in NSCLC patients. However, patients with FHIT hypermethylation had a lower survival rate than those without, HR = 1.73, 95% CI = 1.10-2.71, p = 0.02. The results of this meta-analysis suggest that FHIT hypermethylation is associated with an increased risk and worsen survival in NSCLC patients. FHIT hypermethylation, which induces the inactivation of FHIT gene, plays an important role in the carcinogenesis and clinical outcome and may serve as a potential drug target of NSCLC.
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Chen J, Kwong DL, Cao T, Hu Q, Zhang L, Ming X, Chen J, Fu L, Guan X. Esophageal squamous cell carcinoma (ESCC): advance in genomics and molecular genetics. Dis Esophagus 2015; 28:84-9. [PMID: 23796192 DOI: 10.1111/dote.12088] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Esophageal cancer is aggressive and has poor prognosis. Esophageal squamous cell carcinoma (ESCC) is histologically the most prevalent type of esophageal cancer and ranked as the sixth leading cause of cancer death worldwide. In recent years, cancer has been widely regarded as genetic disease, as well as epigenetic abnormalities including DNA methylation, histone deacetylation, chromatin remodeling, gene imprinting and noncoding RNA regulation. In this review, we will provide a general overview of genes, proteins and microRNAs that are involved in the development of ESCC, which aims to enhance our understanding of molecular mechanisms implicated in ESCC development and progression.
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Affiliation(s)
- J Chen
- Departments of Clinical Oncology, The University of Hong Kong, Hong Kong; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Chen Y, Yin D, Li L, Deng YC, Tian W. Screening aberrant methylation profile in esophageal squamous cell carcinoma for Kazakhs in Xinjiang area of China. Mol Biol Rep 2014; 42:457-64. [DOI: 10.1007/s11033-014-3788-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2013] [Accepted: 09/30/2014] [Indexed: 11/28/2022]
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Cheng CP, Kuo IY, Alakus H, Frazer KA, Harismendy O, Wang YC, Tseng VS. Network-based analysis identifies epigenetic biomarkers of esophageal squamous cell carcinoma progression. ACTA ACUST UNITED AC 2014; 30:3054-61. [PMID: 25015989 DOI: 10.1093/bioinformatics/btu433] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
MOTIVATION A rapid progression of esophageal squamous cell carcinoma (ESCC) causes a high mortality rate because of the propensity for metastasis driven by genetic and epigenetic alterations. The identification of prognostic biomarkers would help prevent or control metastatic progression. Expression analyses have been used to find such markers, but do not always validate in separate cohorts. Epigenetic marks, such as DNA methylation, are a potential source of more reliable and stable biomarkers. Importantly, the integration of both expression and epigenetic alterations is more likely to identify relevant biomarkers. RESULTS We present a new analysis framework, using ESCC progression-associated gene regulatory network (GRN escc), to identify differentially methylated CpG sites prognostic of ESCC progression. From the CpG loci differentially methylated in 50 tumor-normal pairs, we selected 44 CpG loci most highly associated with survival and located in the promoters of genes more likely to belong to GRN escc. Using an independent ESCC cohort, we confirmed that 8/10 of CpG loci in the promoter of GRN escc genes significantly correlated with patient survival. In contrast, 0/10 CpG loci in the promoter genes outside the GRN escc were correlated with patient survival. We further characterized the GRN escc network topology and observed that the genes with methylated CpG loci associated with survival deviated from the center of mass and were less likely to be hubs in the GRN escc. We postulate that our analysis framework improves the identification of bona fide prognostic biomarkers from DNA methylation studies, especially with partial genome coverage.
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Affiliation(s)
- Chun-Pei Cheng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan
| | - I-Ying Kuo
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan
| | - Hakan Alakus
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Ph
| | - Kelly A Frazer
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Ph
| | - Olivier Harismendy
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan
| | - Yi-Ching Wang
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan
| | - Vincent S Tseng
- Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan Department of Computer Science and Information Engineering, National Cheng Kung University, Tainan 701, Taiwan, Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA, Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan, Department of Pediatrics and Rady Children's Hospital, University of California San Diego, La Jolla, CA 92093, USA, Department of General, Visceral and Cancer Surgery, University of Cologne, Köln, Germany, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA, Department of Pharmacology and Institute of Medical Informatics, National Cheng Kung University, Tainan 701, Taiwan
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Molecular alterations and clinical relevance in esophageal squamous cell carcinoma. Front Med 2013; 7:401-10. [PMID: 24002746 DOI: 10.1007/s11684-013-0286-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 07/10/2013] [Indexed: 02/08/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common types of gastrointestinal cancers, and the fourth leading cause of cancer-related deaths in China. Early detection and intervention in time may dramatically increase the survival of the patients by initiating treatment regimens during earlier stages of ESCC or even during precancerous stages. Molecular classification will be useful for subtyping esophageal tumors or precancerous lesions to improve current therapeutics or early intervention of the disease. In this review, we summarize the findings in investigating the molecular alterations and clinical relevance of ESCC.
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Shimizu M, Zaninotto G, Nagata K, Graham DY, Lauwers GY. Esophageal squamous cell carcinoma with special reference to its early stage. Best Pract Res Clin Gastroenterol 2013; 27:171-86. [PMID: 23809239 DOI: 10.1016/j.bpg.2013.03.010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2012] [Accepted: 03/08/2013] [Indexed: 02/07/2023]
Abstract
The term 'early squamous cell carcinoma of the oesophagus', which was previously restricted to superficial carcinoma with no lymph node metastasis, now encompasses intramucosal carcinoma regardless of the nodal status. Such lesions are rare in Western countries, where the experience is limited. In recent years, the development and greater use of chromoendoscopy and narrow band imaging (NBI), both of which facilitate the evaluation of mucosal morphology, have played an important role in the detection of early esophageal squamous cell carcinoma. In addition, the techniques and indications of endoscopic resection (mucosal resection [EMR] and mucosal dissection [ESD]) are still being refined. In the present article, we will discuss the clinical and pathologic features of esophageal early squamous cell carcinoma, as well as the epidemiology and aetiology of esophageal cancer in general. In addition, we will provide a therapeutic decision tree taking into account endoscopic and surgical modalities as they apply to early esophageal squamous cell carcinoma.
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Affiliation(s)
- Michio Shimizu
- Department of Pathology, Saitama Medical University, Saitama International Medical Center, 1397-1 Yamane, Hidaka City, Saitama 350-1298, Japan.
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27
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Baba Y, Watanabe M, Baba H. A review of the alterations in DNA methylation in esophageal squamous cell carcinoma. Surg Today 2013; 43:1355-64. [DOI: 10.1007/s00595-012-0451-y] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2011] [Accepted: 10/26/2012] [Indexed: 12/20/2022]
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Hayashi A, Yashima K, Takeda Y, Sasaki S, Kawaguchi K, Harada K, Murawaki Y, Ito H. Fhit, E-cadherin, p53, and activation-induced cytidine deaminase expression in endoscopically resected early stage esophageal squamous neoplasia. J Gastroenterol Hepatol 2012; 27:1752-8. [PMID: 22742976 DOI: 10.1111/j.1440-1746.2012.07216.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND AND AIM Abnormal expression of Fragile Histidine Triad (Fhit), E-cadherin and p53 is observed in esophageal squamous cell carcinoma. It has recently been reported that aberrant expression of activation-induced cytidine deaminase (AID) in gastric epithelium leads to the accumulation of nucleotide alterations in the p53 gene. However, little is known about the association between these molecular events and the clinicopathological characteristics of early stage esophageal squamous neoplasia, especially in endoscopically resected tumors. METHODS Esophageal squamous neoplasias (n = 49) comprising nine cases of low-grade intraepithelial neoplasia (LGIN), 22 of high-grade intraepithelial neoplasia/carcinoma in situ (HGIN/CIS) and 18 of invasive cancers, were endoscopically resected. Their expression of the tumor-related proteins: Fhit, E-cadherin, p53 and AID was assessed using immunohistochemical methods, and the relationship between protein expression and clinicopathological data was examined. RESULTS Reduced or absent Fhit and E-cadherin expression was detected in 22% and 0% of LGIN cases, 73% and 14% of HGIN/CIS cases, and 94% and 61% of invasive cancer cases, respectively, showing progressive increases during neoplastic progression (Fhit: P < 0.01, E-cadherin: P < 0.01). Although p53 and AID were overexpressed in these samples, no change in their expression occurred during neoplastic progression. Moreover, p53 expression was not significantly associated with AID expression. CONCLUSIONS These results indicate that a decrease in Fhit and E-cadherin expression could be related to the development and progression of esophageal squamous neoplasia, and that the expression of p53 was independent of aberrant AID expression in the early stage of esophageal carcinogenesis.
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Affiliation(s)
- Akihiro Hayashi
- Division of Medicine and Clinical Science, Tottori University, Yonago, Japan
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29
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Li JS, Ying JM, Wang XW, Wang ZH, Tao Q, Li LL. Promoter methylation of tumor suppressor genes in esophageal squamous cell carcinoma. CHINESE JOURNAL OF CANCER 2012; 32:3-11. [PMID: 22572016 PMCID: PMC3845589 DOI: 10.5732/cjc.011.10381] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Esophageal squamous cell carcinoma (ESCC) is a prevalent and fatal cancer in China and other Asian countries. Epigenetic silencing of key tumor suppressor genes (TSGs) is critical to ESCC initiation and progression. Recently, many novel TSGs silenced by promoter methylation have been identified in ESCC, and these genes further serve as potential tumor markers for high-risk group stratification, early detection, and prognosis prediction. This review summarizes recent discoveries on aberrant promoter methylation of TSGs in ESCC, providing better understanding of the role of disrupted epigenetic regulation in tumorigenesis and insight into diagnostic and prognostic biomarkers for this malignancy.
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Affiliation(s)
- Ji-Sheng Li
- Department of Chemotherapy, Shandong University, Jinan, Shandong, People's Republic of China
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30
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Strazzullo M, Corteggio A, Altamura G, Francioso R, Roperto F, D'Esposito M, Borzacchiello G. Molecular and epigenetic analysis of the fragile histidine triad tumour suppressor gene in equine sarcoids. BMC Vet Res 2012; 8:30. [PMID: 22424615 PMCID: PMC3361464 DOI: 10.1186/1746-6148-8-30] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2011] [Accepted: 03/16/2012] [Indexed: 01/14/2023] Open
Abstract
Background Sarcoids are peculiar equine benign tumours. Their onset is associated with Bovine Papillomavirus type -1 or -2 (BPV-1/2) infection. Little is known about the molecular interplay between viral infection and neoplastic transformation. The data regarding papillomavirus infections in human species show the inactivation of a number of tumour suppressor genes as basic mechanism of transformation. In this study the putative role of the tumour suppressor gene Fragile Histidine Triad (FHIT) in sarcoid tumour was investigated in different experimental models. The expression of the oncosuppressor protein was assessed in normal and sarcoid cells and tissue. Results Nine paraffin embedded sarcoids and sarcoid derived cell lines were analysed for the expression of FHIT protein by immunohistochemistry, immunofluorescence techniques and western blotting. These analyses revealed the absence of signal in seven out of nine sarcoids. The two sarcoid derived cell lines too showed a reduced signal of the protein. To investigate the causes of the altered protein expression, the samples were analysed for the DNA methylation profile of the CpG island associated with the FHIT promoter. The analysis of the 32 CpGs encompassing the region of interest showed no significative differential methylation profile between pathological tissues and cell lines and their normal counterparts. Conclusion This study represent a further evidence of the role of a tumour suppressor gene in equine sarcoids and approaches the epigenetic regulation in this well known equine neoplasm. The data obtained in sarcoid tissues and sarcoid derived cell lines suggest that also in horse, as in humans, there is a possible involvement of the tumour suppressor FHIT gene in BPV induced tumours. DNA methylation seems not to be involved in the gene expression alteration. Further studies are needed to understand the basic molecular mechanisms involved in reduced FHIT expression.
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Affiliation(s)
- Maria Strazzullo
- Department of Pathology and Animal Health, University of Naples Federico II, Via Veterinaria, Naples, Italy
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31
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Kaz AM, Grady WM. Epigenetic biomarkers in esophageal cancer. Cancer Lett 2012; 342:193-9. [PMID: 22406828 DOI: 10.1016/j.canlet.2012.02.036] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2012] [Revised: 02/25/2012] [Accepted: 02/29/2012] [Indexed: 12/13/2022]
Abstract
The aberrant DNA methylation of tumor suppressor genes is well documented in esophageal cancer, including adenocarcinoma (EAC) and squamous cell carcinoma (ESCC) as well as in Barrett's esophagus (BE), a pre-malignant condition that is associated with chronic acid reflux. BE is a well-recognized risk factor for the development of EAC, and consequently the standard of care is for individuals with BE to be placed in endoscopic surveillance programs aimed at detecting early histologic changes that associate with an increased risk of developing EAC. Yet because the absolute risk of EAC in individuals with BE is minimal, a clinical need in the management of BE is the identification of additional risk markers that will indicate individuals who are at a significant absolute risk of EAC so that they may be subjected to more intensive surveillance. The best currently available risk marker is the degree of dysplasia in endoscopic biopsies from the esophagus; however, this marker is suboptimal for a variety of reasons. To date, there are no molecular biomarkers that have been translated to widespread clinical practice. The search for biomarkers, including hypermethylated genes, for either the diagnosis of BE, EAC, or ESCC or for risk stratification for the development of EAC in those with BE is currently an area of active research. In this review, we summarize the status of identified candidate epigenetic biomarkers for BE, EAC, and ESCC. Most of these aberrantly methylated genes have been described in the context of early detection or diagnostic markers; others might prove useful for estimating prognosis or predicting response to treatment. Finally, special attention will be paid to some of the challenges that must be overcome in order to develop clinically useful esophageal cancer biomarkers.
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Affiliation(s)
- Andrew M Kaz
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States; Research and Development Service, VA Puget Sound Health Care System, Seattle, WA, United States.
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32
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Zhang XM, Guo MZ. The value of epigenetic markers in esophageal cancer. ACTA ACUST UNITED AC 2010; 4:378-84. [PMID: 21107750 DOI: 10.1007/s11684-010-0230-3] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 10/10/2010] [Indexed: 12/12/2022]
Abstract
Developing esophageal cancer is a multi-step process that begins with the accumulation of genetic and epigenetic alterations, and leads to the activation of oncogenes and the inactivation or loss of tumor suppressor genes (TSG). In addition to genetic alteration, epigenetic modifications, and in particular DNA methylation, are recognized as a common molecular alteration in human tumors. In esophageal cancer, aberrant methylation of promoter regions occurs not only in advanced cancer, but also in premalignant lesions. DNA methylation is related to survival time and sensitivity of chemoradiotherapy. This review is mainly focused on epigenetic changes in esophageal cancer and the value of early detection for patient prognosis, treatment choices, and potential targeting therapy.
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Affiliation(s)
- Xiao-Mei Zhang
- Department of Gastroenterology & Hepatology, Chinese PLA General Hospital, Beijing, 100853, China
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Purdie KJ, Harwood CA, Gibbon K, Chaplin T, Young BD, Cazier JB, Singh N, Leigh IM, Proby CM. High-resolution genomic profiling of human papillomavirus-associated vulval neoplasia. Br J Cancer 2010; 102:1044-51. [PMID: 20234371 PMCID: PMC2844038 DOI: 10.1038/sj.bjc.6605589] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Background: The incidence of human papillomavirus-associated vulval neoplasia is increasing worldwide; yet the associated genetic changes remain poorly understood. Methods: We have used single-nucleotide polymorphism microarray analysis to perform the first high-resolution investigation of genome-wide allelic imbalance in vulval neoplasia. Our sample series comprised 21 high-grade vulval intraepithelial neoplasia and 6 vulval squamous cell carcinomas, with paired non-lesional samples used to adjust for normal copy number variation. Results: Overall the most common recurrent aberrations were gains at 1p and 20, with the most frequent deletions observed at 2q, 3p and 10. Copy-neutral loss of heterozygosity at 6p was a recurrent event in vulval intraepithelial neoplasia. The pattern of genetic alterations differed from the characteristic changes we previously identified in cutaneous squamous cell carcinomas. Vulval neoplasia samples did not exhibit gain at 5p, a frequent recurrent aberration in a series of cervical tumours analysed elsewhere using an identical protocol. Conclusion: This series of 27 vulval samples comprises the largest systematic genome-wide analysis of vulval neoplasia performed to date. Despite shared papillomavirus status and regional proximity, our data suggest that the frequency of certain genetic alterations may differ in vulval and cervical tumours.
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Affiliation(s)
- K J Purdie
- Centre for Cutaneous Research, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK.
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Abstract
DNA methylation plays an important role in regulating normal development and carcinogenesis. Current understanding of the biological roles of DNA methylation is limited to its role in the regulation of gene transcription, genomic imprinting, genomic stability, and X chromosome inactivation. In the past 2 decades, a large number of changes have been identified in cancer epigenomes when compared with normals. These alterations fall into two main categories, namely, hypermethylation of tumor suppressor genes and hypomethylation of oncogenes or heterochromatin, respectively. Aberrant methylation of genes controlling the cell cycle, proliferation, apoptosis, metastasis, drug resistance, and intracellular signaling has been identified in multiple cancer types. Recent advancements in whole-genome analysis of methylome have yielded numerous differentially methylated regions, the functions of which are largely unknown. With the development of high resolution tiling microarrays and high throughput DNA sequencing, more cancer methylomes will be profiled, facilitating the identification of new candidate genes or ncRNAs that are related to oncogenesis, new prognostic markers, and the discovery of new target genes for cancer therapy.
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Affiliation(s)
- Hoi-Hung Cheung
- Section on Developmental Genomics, Laboratory of Clinical Genomics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA
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Lee EJ, Lee BB, Han J, Cho EY, Shim YM, Park J, Kim DH. CpG island hypermethylation of E-cadherin (CDH1) and integrin α4 is associated with recurrence of early stage esophageal squamous cell carcinoma. Int J Cancer 2008; 123:2073-9. [DOI: 10.1002/ijc.23598] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Kim YT, Park JY, Jeon YK, Park SJ, Song JY, Kang CH, Sung SW, Kim JH. Aberrant promoter CpG island hypermethylation of the adenomatosis polyposis coli gene can serve as a good prognostic factor by affecting lymph node metastasis in squamous cell carcinoma of the esophagus. Dis Esophagus 2008; 22:143-50. [PMID: 18847451 DOI: 10.1111/j.1442-2050.2008.00862.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
There has been no clear evidence demonstrating whether DNA hypermethylation can affect the prognosis of esophageal cancer. We collected tissue from 50 cases of squamous cell carcinoma of the esophagus and tested them for DNA hypermethylation using methylation-specific polymerase chain reaction. CpG island hypermethylations were observed in 10% for p16, 34% for RARbetaP2, 46% for adenomatosis polyposis coli (APC), 14% for RASSF1A, 84% for FHIT, and 8% for hMLH1. APC promoter hypermethylation was frequently found in patients without lymph node metastasis compared with those with lymph node metastasis (62.5% : 30.8%, P = 0.025). The number of metastatic lymph nodes were lower in patients with APC promoter hypermethylation (0.87 +/- 0.30 : 3.07 +/- 0.72, P = 0.008). Excluding operative mortalities and incomplete resections, 42 patients were analyzed for long-term outcome. During the mean follow-up period of 35 months, 17 developed recurrence and 14 died of cancer. Ten patients died of other causes. In univariable analysis, unmethylation of APC (P = 0.0015) and FHIT (P = 0.0044), as well as presence of lymph node metastasis (P = 0.0038), were risk factors for recurrence. In multivariable analysis, lymph nodes metastasis (P = 0.050) and unmethylation of APC promoter (P = 0.023) remained as significant risk factors. In conclusion, promoter hypermethylation of the APC gene is related to a lower number of metastatic lymph nodes and to superior prognosis in terms of recurrence, which suggests it might be involved in the process of lymph node metastasis in esophageal cancer.
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Affiliation(s)
- Y T Kim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea.
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Gray SE, Kay E, Leader M, Mabruk M. Analysis ofFHITallelic imbalance/loss of heterozygosity and FHIT expression in cutaneous squamous cell carcinomas. J Cutan Pathol 2008; 35:816-25. [DOI: 10.1111/j.1600-0560.2007.00913.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Ki KD, Lee SK, Tong SY, Lee JM, Song DH, Chi SG. Role of 5'-CpG island hypermethylation of the FHIT gene in cervical carcinoma. J Gynecol Oncol 2008; 19:117-22. [PMID: 19471558 DOI: 10.3802/jgo.2008.19.2.117] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2008] [Revised: 05/30/2008] [Accepted: 06/09/2008] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVE The abnormal expression of fragile histidine triad (FHIT) gene has been frequently reported in a variety of epithelial malignancies including cervical carcinoma. Furthermore, in a recent study it was proposed that transcriptional inactivation of FHIT, as a consequence of aberrant 5'-CpG island methylation, plays an important role in the carcinogenesis of human cervical carcinoma. The authors sought to determine whether abnormal FHIT transcription occurs in human cervical carcinoma, and if so, whether this abnormal expression is associated with aberrant 5'-CpG island methylation. In addition, the clinical significance of FHIT inactivation was investigated in Korean women with cervical cancer. METHODS To examine for abnormal transcripts of the FHIT gene, quantitative RT-PCR, genomic DNA-PCR and nonisotopic RT-PCR-SSCP analysis were performed using the standard method. The methylation status was determined by methylation specific PCR and bisulfite DNA sequencing. RESULTS The FHIT gene was down-regulated in 15 of 58 (25.9%) cervical carcinomas. FHIT promoter hypermethylation was detected in 15 of 15 (100%) abnormally expression in cervical carcinomas. Bisulfite DNA sequencing confirmed these findings and a significant correlation was found between CpG site hypermethylation and low FHIT expression. However, no significant correlation was found between reduced FHIT expression and clinicopathological characteristics. CONCLUSION In this study, FHIT inactivation in cervical cancer was found to be strongly correlated with 5'-CpG island hypermethylation rather than a genetic alteration. Furthermore, no significant relation was found between a lack of FHIT expression and the prognostic factors of cervical cancer in our Korean cohort.
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Affiliation(s)
- Kyung-Do Ki
- Department of Obstetrics and Gynecology, East-West Neo Medical Center, Kyung-Hee University, Korea
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Hypermethylation of the 5'CpG island of the FHIT gene in clear cell renal carcinomas. Cancer Lett 2008; 265:250-7. [PMID: 18378390 DOI: 10.1016/j.canlet.2008.02.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2007] [Revised: 02/08/2008] [Accepted: 02/11/2008] [Indexed: 11/21/2022]
Abstract
FHIT is a tumour suppressor gene which is frequently inactivated in different types of cancer. Both genetic (mutations, deletions, chromosomal rearrangements) and epigenetic (aberrant methylation of the 5'CpG island) alterations of the FHIT gene have been reported in various malignancies. Yet little is known about the mechanism of FHIT inactivation in clear cell renal carcinomas. Since genetic alterations were not frequently observed in DNA corresponding to the FHIT gene in renal tumours, to elucidate the mechanism of FHIT gene silencing we examined 22 paired samples of clear cell renal carcinoma and non-malignant renal tissue for the methylation of the FHIT 5'CpG island by methylation-specific PCR. Hypermethylation of the FHIT 5'CpG island was detected in 54.5% (12/22) of clear cell renal carcinomas. Bisulfite sequencing of the FHIT 5'CpG island confirmed the results obtained by methylation-specific PCR for selected samples. We showed here that expression of the FHIT gene is inversely correlated with hypermethylation of the FHIT 5'CpG island in the selected samples. Our results suggest that hypermethylation of the FHIT 5'CpG island may be responsible for inactivation of the FHIT gene in clear cell renal carcinomas.
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Jin Z, Olaru A, Yang J, Sato F, Cheng Y, Kan T, Mori Y, Mantzur C, Paun B, Hamilton JP, Ito T, Wang S, David S, Agarwal R, Beer DG, Abraham JM, Meltzer SJ. Hypermethylation of tachykinin-1 is a potential biomarker in human esophageal cancer. Clin Cancer Res 2008; 13:6293-300. [PMID: 17975140 DOI: 10.1158/1078-0432.ccr-07-0818] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Our aim was to investigate whether and at what stage hypermethylation of the tachykinin-1 (TAC1) gene is associated with human esophageal neoplastic transformation. EXPERIMENTAL DESIGN TAC1 promoter hypermethylation was examined by real-time methylation-specific PCR in 258 human esophageal specimens and 126 plasma samples from patients or tissues at various stages of neoplastic evolution. RESULTS TAC1 hypermethylation in tissue samples showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC) from normal esophagus (P < 0.0001). Both frequencies and normalized methylation values of TAC1 tissue methylation were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's esophagus, EAC, and ESCC than in normal esophagus (P < 0.01). The frequency of TAC1 hypermethylation increased dramatically and early during neoplastic progression, from 7.5% in normal esophagus to 55.6% in BE from patients with Barrett's metaplasia alone, 57.5% in dysplastic Barrett's esophagus, and 61.2% in EAC. There was a significant relationship between TAC1 hypermethylation and BE segment length, a known clinical risk factor for neoplastic progression. Twelve (50%) of 24 ESCC exhibited TAC1 hypermethylation. Overall patient survival correlated significantly with TAC1 methylation status in ESCC patients (mean survival, 22 versus 110 months; P = 0.0102, log-rank test), but not in EAC patients. Both mean normalized methylation values and frequency of TAC1 hypermethylation in plasma samples were significantly higher in EAC patients than in control subjects. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced TAC1 methylation and increased TAC1 mRNA expression. CONCLUSIONS TAC1 promoter hypermethylation is a common event in both major histologic types of human esophageal carcinoma, occurs early, correlates with other progression risk factors in esophageal adenocarcinogenesis, and is a tissue biomarker of a poor prognosis in ESCC. Circulating methylated TAC1 promoter DNA also offers potential as a biomarker for the diagnosis of EAC.
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Affiliation(s)
- Zhe Jin
- Division of Gastroenterology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Jin Z, Mori Y, Yang J, Sato F, Ito T, Cheng Y, Paun B, Hamilton JP, Kan T, Olaru A, David S, Agarwal R, Abraham JM, Beer D, Montgomery E, Meltzer SJ. Hypermethylation of the nel-like 1 gene is a common and early event and is associated with poor prognosis in early-stage esophageal adenocarcinoma. Oncogene 2007; 26:6332-40. [PMID: 17452981 DOI: 10.1038/sj.onc.1210461] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The nel-like1 (NELL1) gene maps to chromosome 11p15, which frequently undergoes loss of heterozygosity in esophageal adenocarcinoma (EAC). NELL1 promoter hypermethylation was examined by real-time methylation-specific polymerase chain reaction in 259 human esophageal tissues. Hypermethylation of this promoter showed highly discriminative receiver-operator characteristic curve profiles, clearly distinguishing esophageal squamous cell carcinoma (ESCC) and EAC from normal esophagus (NE) (P<0.001). NELL1 normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's (D) and EAC than in NE (P<0.0000001). NELL1 hypermethylation frequency was zero in NE but increased early during neoplastic progression, to 41.7% in BE from patients with Barrett's alone, 52.5% in D and 47.8% in EAC. There was a significant correlation between NELL1 hypermethylation and BE segment length. Three (11.5%) of 26 ESCCs exhibited NELL1 hypermethylation. Survival correlated inversely with NELL1 hypermethylation in patients with stages I-II (P=0.0264) but not in stages III-IV (P=0.68) EAC. Treatment of KYSE220 ESCC and BIC EAC cells with 5-aza-2'-deoxycytidine reduced NELL1 methylation and increased NELL1 mRNA expression. NELL1 mRNA levels in EACs with an unmethylated NELL1 promoter were significantly higher than those in EACs with a methylated promoter (P=0.02). Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC.
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Affiliation(s)
- Z Jin
- Division of Gastroenterology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA
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Kujan O, Oliver R, Roz L, Sozzi G, Ribeiro N, Woodwards R, Thakker N, Sloan P. Fragile Histidine Triad Expression in Oral Squamous Cell Carcinoma and Precursor Lesions. Clin Cancer Res 2006; 12:6723-9. [PMID: 17121892 DOI: 10.1158/1078-0432.ccr-06-1475] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Fragile histidine triad (FHIT) expression in precursor oral lesions (POL) and oral squamous cell carcinomas (OSCC) was studied with regard to (a) the frequency of loss of FHIT expression, (b) whether loss of FHIT expression correlates with degree of dysplasia in POLs, (c) whether FHIT loss predicts high-risk POLs that are more likely to transform, and (d) whether FHIT loss in OSCCs correlates with survival. EXPERIMENTAL DESIGN Ninety-four POLs and 86 OSCCs were immunostained for FHIT. Survival analysis was done for cases with validated clinical outcomes. RESULTS By optimizing the immunostaining protocol, we found that FHIT is expressed in a distinctive strong nuclear and weak cytoplasmic pattern in oral tissues. Loss of FHIT expression was found in 42 of 94 (45%) POLs and in 66 of 86 (77%) OSCCs. We observed a statistically significant positive correlation between frequency of FHIT loss and increasing grade of dysplasia (chi2=13.8; degrees of freedom=4; P=0.008). Loss of FHIT expression in POLs that progressed to malignancy was more frequent than in those that did not [17 of 25 (68%) versus 12 of 29 (41.4%), respectively]. This difference was statistically significant (chi2=3.8; degrees of freedom=1; P=0.046). In OSCCs, loss of FHIT staining indicated a worse prognosis (survival rate, 36.2%) than when positive FHIT staining was observed (survival rate, 50%), but the difference was not statistically significant (P=0.546, Kaplan-Meier, log-rank). CONCLUSIONS FHIT seems to localize to both nuclear and cytoplasmic domains. FHIT inactivation occurs early in oral carcinogenesis and may be useful molecular marker for progressive dysplastic oral lesions.
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Affiliation(s)
- Omar Kujan
- School of Dentistry, The University of Manchester, North Manchester General Hospital, UK
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Abstract
Genetic abnormalities of proto-oncogenes and tumor suppressor genes have been demonstrated to be changes that are frequently involved in esophageal cancer pathogenesis. However, hypermethylation of CpG islands, an epigenetic event, is coming more and more into focus in carcinogenesis of the esophagus. Recent studies have proved that promoter hypermethylation of tumor suppressor genes is frequently observed in esophageal carcinomas and seems to play an important role in the pathogenesis of this tumor type. In this review, we will discuss current research on genes that are hypermethylated in human esophageal cancer and precancerous lesions of the esophagus. We will also discuss the potential use of hypermethylated genes as targets for detection, prognosis and treatment of esophageal cancer.
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Affiliation(s)
- Da-Long Wu
- Department of Pharmacology, School of Medicine, College of Jiaxing, Jiaxing 314001, Zhejiang Province, China.
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Smith DI, McAvoy S, Zhu Y, Perez DS. Large common fragile site genes and cancer. Semin Cancer Biol 2006; 17:31-41. [PMID: 17140807 DOI: 10.1016/j.semcancer.2006.10.003] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2006] [Revised: 09/07/2006] [Accepted: 10/17/2006] [Indexed: 12/01/2022]
Abstract
The common fragile sites are large regions of genomic instability that are found in all individuals and are hot spots for chromosomal rearrangements and deletions. A number of the common fragile sites have been found to span genes that are encoded by very large genomic regions. Two of these genes, FHIT and WWOX, have already been demonstrated to function as tumor suppressors. In this review we will discuss the large common fragile site genes that have been identified to date, and the role that these genes appear to play both in cellular responses to stress and in the development of cancer.
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Affiliation(s)
- David I Smith
- Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street, S.W., Rochester, MN 55905, United States.
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