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Yue C, Zhang Y, Wang Y, Zhang Z, Zhang M, Wang H, Chen W, Shang Z, Xin Y, Zhang X, Zhang Y. The Application Value of Syndecan-2 Gene Methylation for Colorectal Cancer Diagnosis: A Clinical Study and Meta-Analyses. Front Med (Lausanne) 2022; 9:753545. [PMID: 35372441 PMCID: PMC8964598 DOI: 10.3389/fmed.2022.753545] [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: 08/05/2021] [Accepted: 02/07/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Syndecan-2 (SDC2) methylation has been previously reported as a sensitive biomarker for the early detection of colorectal cancer (CRC). Droplet digital PCR (ddPCR) is the latest development of PCR technology. It can accurately detect and quantify the target sequence of nucleic acid. ddPCR is widely used in research and clinical diagnosis. In the present study, we aimed to develop a ddPCR method to detect SDC2 gene methylation and evaluate the diagnostic value of SDC2 gene methylation. Methods First, a ddPCR method was developed to measure SDC2 methylation in stool samples collected from 51 cases of normal, 23 cases of adenoma, and 86 cases of CRC. Subsequently, a meta-analysis of existing studies was conducted to judge the diagnostic value of SDC2 gene methylation in CRC. PUBMED, EMBASE, Web of Science, and Scopus databases were searched for relative studies. Meta-analysis was performed using Meta Disc 1.4 and STATA 15.0 software. Results The ddPCR showed that the linearity, sensitivity, and specificity for the detection of SDC2 gene methylation could be down to 0.1% methylation level and 5 ng of methylated DNA input. In 109 cases of CRC, 107 cases could be detected, and the sensitivity was 98.17%. The median value of the percentage of methylated reference (PMR) in colorectal adenoma and CRC patients was significantly higher compared with the normal individuals (p < 0.001). In addition, we found that the PMR value was associated with the clinical staging of CRC. The difference of PMR in stage II and stage IIIA was statistically significant (p < 0.05). Moreover, the meta-analysis showed that 11 out of 87 studies were identified to report the feasibility of SDC2 gene methylation as a method to diagnose early CRC. The pooled sensitivity and specificity of SDC2 gene methylation test for CRC were 0.80 [95% CI (0.68–0.88)] and 0.93 [95% CI (0.91–0.94)], respectively. The pooled diagnostic odds ratio (DOR) and area under curve (AUC) were 52.46 [95% CI (30.43–90.45)] and 0.94 [95% CI (0.92, 0.96)], respectively. Conclusions The ddPCR method was more sensitive and convenient to detect SDC2 gene methylation, and the pooled analysis showed that methylated SDC2 was a valuable biomarker for the non-invasive detection of CRC.
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Affiliation(s)
- Congbo Yue
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yaping Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yanlei Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | | | - Mengjiao Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Huayang Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Wendan Chen
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Ziqi Shang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yiwei Xin
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
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Rademakers G, Massen M, Koch A, Draht MX, Buekers N, Wouters KAD, Vaes N, De Meyer T, Carvalho B, Meijer GA, Herman JG, Smits KM, van Engeland M, Melotte V. Identification of DNA methylation markers for early detection of CRC indicates a role for nervous system-related genes in CRC. Clin Epigenetics 2021; 13:80. [PMID: 33858496 PMCID: PMC8048074 DOI: 10.1186/s13148-021-01067-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Accepted: 04/04/2021] [Indexed: 12/17/2022] Open
Abstract
Purpose Colonoscopy and the fecal immunochemical test (FIT) are currently the most widely used screening modalities for colorectal cancer (CRC), however, both with their own limitations. Here we aim to identify and validate stool-based DNA methylation markers for the early detection of CRC and investigate the biological pathways prone to DNA methylation. Methods DNA methylation marker discovery was performed using The Cancer Genome Atlas (TCGA) colon adenocarcinoma data set consisting of normal and primary colon adenocarcinoma tissue. The performance of the five best candidate markers and a previously identified marker, NDRG4, was evaluated on tissues and whole stool samples of healthy subjects and CRC patients using quantitative MSP assays. The results were compared and combined with FIT data. Finally, pathway and gene ontology enrichment analyses were performed using ToppFun, GOrilla and clusterProfiler. Results GDNF, HAND2, SLC35F3, SNAP91 and SORCS1 were ranked as the best performing markers. Gene combinations of all five markers, NDRG4 and FIT were evaluated to establish the biomarker panel with the highest diagnostic potential, resulting in the identification of GDNF/SNAP91/NDRG4/FIT as the best performing marker panel. Pathway and gene ontology enrichment analyses revealed that genes associated with the nervous system were enriched in the set of best performing CRC-specific biomarkers. Conclusion In silico discovery analysis using TCGA-derived data yielded a novel DNA-methylation-based assay for the early detection of CRC, potentially improving current screening modalities. Additionally, nervous system-related pathways were enriched in the identified genes, indicating an epigenetic regulation of neuronal genes in CRC. Supplementary Information The online version contains supplementary material available at 10.1186/s13148-021-01067-9.
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Affiliation(s)
- Glenn Rademakers
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Maartje Massen
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Alexander Koch
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Muriel X Draht
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Nikkie Buekers
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Kim A D Wouters
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Nathalie Vaes
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Tim De Meyer
- Department of Data Analysis and Mathematical Modelling, Ghent University, Ghent, Belgium
| | - Beatriz Carvalho
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Gerrit A Meijer
- Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
| | - Kim M Smits
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Manon van Engeland
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Veerle Melotte
- Department of Pathology, GROW - School for Oncology and Developmental Biology, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. .,Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
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Chauvin A, Boisvert FM. Clinical Proteomics in Colorectal Cancer, a Promising Tool for Improving Personalised Medicine. Proteomes 2018; 6:proteomes6040049. [PMID: 30513835 PMCID: PMC6313903 DOI: 10.3390/proteomes6040049] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/22/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is the third most common and the fourth most lethal cancer worldwide. In most of cases, patients are diagnosed at an advanced or even metastatic stage, thus explaining the high mortality. The lack of proper clinical tests and the complicated procedures currently used for detecting this cancer, as well as for predicting the response to treatment and the outcome of a patient's resistance in guiding clinical practice, are key elements driving the search for biomarkers. In the present overview, the different biomarkers (diagnostic, prognostic, treatment resistance) discovered through proteomics studies in various colorectal cancer study models (blood, stool, biopsies), including the different proteomic techniques used for the discovery of these biomarkers, are reviewed, as well as the various tests used in clinical practice and those currently in clinical phase. These studies define the limits and perspectives related to proteomic biomarker research for personalised medicine in colorectal cancer.
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Affiliation(s)
- Anaïs Chauvin
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
| | - François-Michel Boisvert
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
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Lee PY, Chin SF, Low TY, Jamal R. Probing the colorectal cancer proteome for biomarkers: Current status and perspectives. J Proteomics 2018; 187:93-105. [PMID: 29953962 DOI: 10.1016/j.jprot.2018.06.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/13/2018] [Accepted: 06/23/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Biomarkers that can facilitate better clinical management of CRC are in high demand to improve patient outcome and to reduce mortality. In this regard, proteomic analysis holds a promising prospect in the hunt of novel biomarkers for CRC and in understanding the mechanisms underlying tumorigenesis. This review aims to provide an overview of the current progress of proteomic research, focusing on discovery and validation of diagnostic biomarkers for CRC. We will summarize the contributions of proteomic strategies to recent discoveries of protein biomarkers for CRC and also briefly discuss the potential and challenges of different proteomic approaches in biomarker discovery and translational applications.
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Affiliation(s)
- Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia.
| | - Siok-Fong Chin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
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Abstract
PURPOSE OF REVIEW Patients with long-standing ulcerative colitis have an increased risk for the development of colorectal cancer (CRC). Colitis-related dysplasia appears to confer the greatest risk. Colonoscopic surveillance to detect dysplasia has been advocated by gastrointestinal societies. The aim of surveillance is the reduction of mortality and morbidity of CRC through detection and resection of dysplasia or detecting CRC at an earlier and potentially curable stage. Traditional surveillance has relied on mucosal assessment with targeted biopsy of visible lesions and random biopsy sampling on the premise that dysplasia was not visible at endoscopy. Advances in optical technology permitting increased detection of dysplasia and evidence that most dysplasia is visible has had practice-changing implications. RECENT FINDINGS Emerging evidence favours chromoendoscopy (CE) for dysplasia detection and is gaining wider acceptance through recent international (International Consensus Statement on Surveillance and Management of Dysplasia in Inflammatory Bowel Disease (SCENIC)) recommendations and endorsed by many gastrointestinal societies. Adoption of CE as the gold standard of surveillance has been met with by scepticism, from conflicting data, operational barriers and the need to understand the true impact of increasingly higher dysplasia detection on overall CRC mortality. Valid debate notwithstanding, implementation of a risk stratification protocol that includes CE is an effective approach allowing earlier detection of dysplasia and colorectal neoplasia, determination of surveillance intervals with appropriate allocation of resources and limiting morbidity from CRC and colonoscopy itself. Further prospective data should define the true and long-term impact of dysplasia detection with modern techniques.
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6
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Cancer molecular markers: A guide to cancer detection and management. Semin Cancer Biol 2018; 52:39-55. [PMID: 29428478 DOI: 10.1016/j.semcancer.2018.02.002] [Citation(s) in RCA: 43] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Revised: 11/04/2017] [Accepted: 02/05/2018] [Indexed: 02/07/2023]
Abstract
Cancer is generally caused by the molecular alterations which lead to specific mutations. Advances in molecular biology have provided an impetus to the study of cancers with valuable prognostic and predictive significance. Over the hindsight various attempts have been undertaken by scientists worldwide, in the management of cancer; where, we have witnessed a number of molecular markers which allow the early detection of cancers and lead to a decrease in its mortality rate. Recent advances in oncology have led to the discovery of cancer markers that has allowed early detection and targeted therapy of tumors. In this context, current review provides a detail outlook on various molecular markers for diagnosis, prognosis and management of therapeutic response in cancer patients.
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Beintaris I, Rutter M. Advanced imaging in colonoscopy: contemporary approach to dysplasia surveillance in inflammatory bowel disease. Frontline Gastroenterol 2016; 7:308-315. [PMID: 28839872 PMCID: PMC5369495 DOI: 10.1136/flgastro-2016-100735] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 07/19/2016] [Indexed: 02/04/2023] Open
Abstract
Inflammatory bowel disease (IBD) (ulcerative colitis (UC) and Crohn's disease (CD)) is a chronic relapsing/remitting condition characterised by intestinal inflammation. One of the main concerns in patients with longstanding ulcerative and Crohn's colitis is development of colonic dysplasia and colorectal cancer (CRC), a risk higher than that of the general population. Colonoscopy surveillance programmes have been developed by major societies worldwide to improve early dysplasia detection and treatment, thus preventing progression to colorectal cancer. Colonoscopy is an imperfect tool as lesions can be missed, an issue even more relevant to colitic patients, where mucosal inspection and lesion recognition may prove challenging. Extensive research has been undertaken on performance improvement in this area while technical advances in optical imaging, such as high-definition, have made their way into modern endoscopy units. Techniques and technologies available to enhance optical diagnosis of dysplasia in inflammatory bowel disease are reviewed in this paper, focusing on those that are realistic, widely available and feasible for everyday practice.
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Affiliation(s)
| | - Matt Rutter
- University Hospital of North Tees, Cleveland, UK
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8
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Armengol G, Sarhadi VK, Ghanbari R, Doghaei-Moghaddam M, Ansari R, Sotoudeh M, Puolakkainen P, Kokkola A, Malekzadeh R, Knuutila S. Driver Gene Mutations in Stools of Colorectal Carcinoma Patients Detected by Targeted Next-Generation Sequencing. J Mol Diagn 2016; 18:471-9. [PMID: 27155048 DOI: 10.1016/j.jmoldx.2016.01.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Revised: 11/25/2015] [Accepted: 01/20/2016] [Indexed: 12/13/2022] Open
Abstract
Detection of driver gene mutations in stool DNA represents a promising noninvasive approach for screening colorectal cancer (CRC). Amplicon-based next-generation sequencing (NGS) is a good option to study mutations in many cancer genes simultaneously and from a low amount of DNA. Our aim was to assess the feasibility of identifying mutations in 22 cancer driver genes with Ion Torrent technology in stool DNA from a series of 65 CRC patients. The assay was successful in 80% of stool DNA samples. NGS results showed 83 mutations in cancer driver genes, 29 hotspot and 54 novel mutations. One to five genes were mutated in 75% of cases. TP53, KRAS, FBXW7, and SMAD4 were the top mutated genes, consistent with previous studies. Of samples with mutations, 54% presented concomitant mutations in different genes. Phosphatidylinositol 3-kinase/mitogen-activated protein kinase pathway genes were mutated in 70% of samples, with 58% having alterations in KRAS, NRAS, or BRAF. Because mutations in these genes can compromise the efficacy of epidermal growth factor receptor blockade in CRC patients, identifying mutations that confer resistance to some targeted treatments may be useful to guide therapeutic decisions. In conclusion, the data presented herein show that NGS procedures on stool DNA represent a promising tool to detect genetic mutations that could be used in the future for diagnosis, monitoring, or treating CRC.
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Affiliation(s)
- Gemma Armengol
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Unit of Biological Anthropology, Department of Animal Biology, Plant Biology and Ecology, Autonomous University of Barcelona, Barcelona, Spain
| | - Virinder K Sarhadi
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Reza Ghanbari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Reza Ansari
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Sasan Alborz Biomedical Research Center, Masoud Clinic, Tehran, Iran
| | - Masoud Sotoudeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Sasan Alborz Biomedical Research Center, Masoud Clinic, Tehran, Iran
| | - Pauli Puolakkainen
- Gastrointestinal Clinic, The University Central Hospital of Helsinki, Helsinki, Finland
| | - Arto Kokkola
- Gastrointestinal Clinic, The University Central Hospital of Helsinki, Helsinki, Finland
| | - Reza Malekzadeh
- Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Sasan Alborz Biomedical Research Center, Masoud Clinic, Tehran, Iran
| | - Sakari Knuutila
- Department of Pathology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Annaházi A, Ábrahám S, Farkas K, Rosztóczy A, Inczefi O, Földesi I, Szűcs M, Rutka M, Theodorou V, Eutamene H, Bueno L, Lázár G, Wittmann T, Molnár T, Róka R. A pilot study on faecal MMP-9: a new noninvasive diagnostic marker of colorectal cancer. Br J Cancer 2016; 114:787-792. [PMID: 26908323 PMCID: PMC4984857 DOI: 10.1038/bjc.2016.31] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 01/06/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one of the leading malignancies worldwide, therefore cheap noninvasive screening methods are of great importance. Matrix-metalloproteinase-9 (MMP-9) has a role in the progression of CRC, and its level is elevated in tumour biopsies. Faecal MMP-9 levels are increased in active ulcerative colitis patients, but in CRC patients, they have never been measured. We aimed to assess the faecal MMP-9 levels in patients undergoing total colonoscopy according to endoscopic and histological diagnosis. METHODS One hundred and nine patients provided faecal samples for MMP-9 analysis. A total colonoscopy was performed; suspicious lesions were evaluated by histology. Faecal MMP-9 levels were measured by ELISA. RESULTS The number of patients allocated to different groups were: negative/diverticulosis: 34 (referred to as controls); hyperplastic polyps: 15; adenomas: 32 (22 at high risk); and CRC: 28. Faecal MMP-9 was significantly increased in CRC compared with all other groups (P<0.001). Faecal MMP-9 was suitable to distinguish CRC patients from controls (sensitivity: 89.3%; specificity: 91.2%). By means of a lower cutoff level, faecal MMP-9 identified high-risk adenomas besides CRC (sensitivity: 76%; specificity: 85.3%). This lower cutoff level screened 59% of high-risk adenomas. CONCLUSIONS Faecal MMP-9 may be a promising new noninvasive marker in CRC.
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Affiliation(s)
- Anita Annaházi
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Szabolcs Ábrahám
- Department of Surgery, University of Szeged, Pf. 427, Szeged 6701, Hungary
| | - Klaudia Farkas
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - András Rosztóczy
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Orsolya Inczefi
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Imre Földesi
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Mónika Szűcs
- Department of Medical Physics and Informatics, University of Szeged, Korányi Fasor 9, Szeged 6720, Hungary
| | - Mariann Rutka
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Vassilia Theodorou
- Toxalim UMR 1331 INRA/INP/UPS, Neuro-Gastroenterology and Nutrition Unit, 180, Chemin de Tournefeuille, BP.93173, Toulouse Cedex 3, 31027, France
| | - Helene Eutamene
- Toxalim UMR 1331 INRA/INP/UPS, Neuro-Gastroenterology and Nutrition Unit, 180, Chemin de Tournefeuille, BP.93173, Toulouse Cedex 3, 31027, France
| | - Lionel Bueno
- Toxalim UMR 1331 INRA/INP/UPS, Neuro-Gastroenterology and Nutrition Unit, 180, Chemin de Tournefeuille, BP.93173, Toulouse Cedex 3, 31027, France
| | - György Lázár
- Department of Surgery, University of Szeged, Pf. 427, Szeged 6701, Hungary
| | - Tibor Wittmann
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Tamás Molnár
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
| | - Richárd Róka
- First Department of Medicine, University of Szeged, Korányi Fasor 8-10, Szeged 6720, Hungary
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Vatandoost N, Ghanbari J, Mojaver M, Avan A, Ghayour-Mobarhan M, Nedaeinia R, Salehi R. Early detection of colorectal cancer: from conventional methods to novel biomarkers. J Cancer Res Clin Oncol 2016; 142:341-51. [PMID: 25687380 DOI: 10.1007/s00432-015-1928-z] [Citation(s) in RCA: 85] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 01/23/2015] [Indexed: 02/06/2023]
Abstract
PURPOSE Colorectal cancer (CRC) is one of the major health problems worldwide and is often diagnosed at late stage. There is growing body of evidence in early detection of this disease with novel screening modalities to reduce compliance and increase specificity of available methods. The aim of current review is to give an overview on currently available screening methods (e.g., fecal occult blood testing (FOBT), flexible sigmoidoscopy, and colonoscopy), with their own merits and disadvantages, and new genetic/epigenetic/protein markers, as novel screening modalities. RESULT There are several serum and fecal biomarkers that can predict CRC and polyps. Overall sensitivities for detection by fecal DNA markers ranged from 53 to 87%, while a panel of serum protein markers provides a sensitivity/specificity up to 85% for CRC. In particular, DNA methylation markers (e.g., SEPT9, SFRP2, and ALX4), circulating microRNAs (e.g., microRNA21), SNPs in microRNAs binding site (e.g., rs4596 located within a target region of the predicted miR-518a-5p and miR-527), protein markers (e.g., carcinoembryonic antigen, N-methyltransferase), or microsatellites instability in tumors with deficient mismatch repair of some genes are among the most interesting and promising biomarkers. CONCLUSION Increasing evidence supports the use of combined fecal and serum biomarkers with sigmoidoscopy and colonoscopy screening in order to maximize the benefits and reduce the number of false-positive tests and patients undergoing invasive methods, which in turn could overcome the limitations of the current screening methods for early detection of CRC and adenomas.
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Affiliation(s)
- Nasimeh Vatandoost
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Jahanafrooz Ghanbari
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahboobeh Mojaver
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Amir Avan
- Molecular Medicine Group, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Biochemistry of Nutrition Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Reza Nedaeinia
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.
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Barat A, Ruskin HJ. Comparative Correlation Structure of Colon Cancer Locus Specific Methylation: Characterisation of Patient Profiles and Potential Markers across 3 Array-Based Datasets. J Cancer 2015; 6:795-811. [PMID: 26185542 PMCID: PMC4504116 DOI: 10.7150/jca.9883] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Accepted: 04/02/2015] [Indexed: 12/18/2022] Open
Abstract
Abnormal DNA-methylation is well known to play an important role in cancer onset and development, and colon cancer is no exception to this rule. Recent years have seen the increased use of large-scale technologies, (such as methylation microarray assays or specific sequencing of methylated DNA), to determine whole genome profiles of CpG island methylation in tissue samples. Comprehensive study of methylation array data from transcriptome high-throughput platforms permits determination of gene methylation markers, important for cancer profiling. Here, three large-scale methylation datasets for colon cancer have been compared to determine locus-specific methylation agreement. These data are from the GEO database, where colon cancer and apparently healthy adjacent tissues are represented by sample sizes 125 and 29 respectively in the first dataset, 24 of each in the second and 118 of each in the third. Several data analysis techniques have been employed, including Clustering, Discriminant Principal Component Analysis, Discriminant Analysis and ROC curves, in order (i) to obtain a better insight on the locus-specific concomitant methylation structures for these diverse data and (ii) to determine a robust potential marker set for indicative screening, drawn from all data taken together. The extent of the agreement between the analysed datasets is reported. Further, potential screening methylation markers, for which methylation profiles are consistent across tissue samples and several datasets, are highlighted and discussed.
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Affiliation(s)
- Ana Barat
- Centre for Scientific Computing and Complex Systems Modelling (Sci-Sym), School of Computing, Dublin City University, Ireland
| | - Heather J Ruskin
- Centre for Scientific Computing and Complex Systems Modelling (Sci-Sym), School of Computing, Dublin City University, Ireland
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12
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Abstract
Screening for premalignant lesions or early invasive disease has the potential to reduce mortality from cancer. Because of their ease of measurement, several biomarkers have been evaluated or are currently undergoing evaluation as screening tests for early malignancy. These include the use of AFP in screening for hepatocellular cancer in high-risk subjects, CA 125 in combination with transvaginal ultrasound (TVU) in screening for epithelial ovarian cancer, PSA in screening for prostate cancer, faecal occult blood testing (FOBT) in screening for colorectal cancer (CRC) and vanillymandelic acid and homovanillic acid in screening for neuroblastoma in newborn infants, Of these biomarkers, only the use of FOBT in screening for CRC has unequivocally been shown to reduce mortality from cancer. Although 2 large randomized prospective trials have evaluated PSA as a screening test for prostate cancer, it is still unclear whether the benefits outweigh the harms in this setting. Although biomarkers have many attractive features as cancer screening tests, lack of sensitivity and specificity, when combined with the low prevalence of specific cancer types in asymptomatic subjects, limit their application for the early detection of malignancy.
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Affiliation(s)
- Michael J Duffy
- Clinical Research Centre, St Vincent's University Hospital, Elm Park, Dublin, 4, Ireland.
- UCD School of Medicine and Medical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, 4, Ireland.
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Wang J, Yu H, Ye L, Jin L, Yu M, Lv Y. Integrated regulatory mechanisms of miRNAs and targeted genes involved in colorectal cancer. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:517-529. [PMID: 25755742 PMCID: PMC4348893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Accepted: 12/22/2014] [Indexed: 06/04/2023]
Abstract
PURPOSE CRC (Colorectal cancer) is a lethal cancer for death worldwide and the underlying pathological mechanisms for CRC progression remain unclear. We aimed to explore the regulatory mechanism of CRC and provide novel biomarkers for CRC screening. METHODS Downloading from GEO (Gene Expression Omnibus) database, Microarray data GSE44861 were consisted of 111 colon tissues samples including 55 from adjacent noncancerous tissues and 56 from tumors tissues. After data pre-processing, up- and down regulated DEGs (differentially expressed genes) were identified using Bayes moderated t-test. Then DIVAD (Database for Annotation, Visualization and Integrated Discovery) was recruited to perform functional analysis for DEGs. Thereafter, PPI (protein-protein interaction) network was constructed by mapping DEGs into STRING (Search Tool for the Retrieval of Interacting Genes) database. Further, PPI modules were constructed and the protein domains of DEGs in the modules were analyzed. Moreover, miRNA regulatory network was established through GSEA (gene set enrichment analysis) method. RESULTS In summary, 96 up- and 212 down-regulated DEGs were identified. Totally, ten DEGs with high degrees in the constructed PPI network were selected, in which COLL1A1, PTGS2 and ASPN were also identified as crucial genes in PPI modules. Furthermore, COLL1A1 was predicted to be targeted by miR-29, while PTGS2 and ASPN were both predicted to be regulated by miR-101 and miR-26. CONCLUSION COL11A1 might involve in the progression of CRC via being targeted by miR-29, whereas PTGS2 and ASPN were both regulated by miR-101 and miR-26. Moreover, ASPN may be supposed as a novel biomarker for CRC detection and prevention.
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Affiliation(s)
- Jianxin Wang
- Department of Anorectal Surgery, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
| | - Hualong Yu
- Department of Anorectal Surgery, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
| | - Lan Ye
- Department of Oncology, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
| | - Lei Jin
- Department of Anorectal Surgery, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
| | - Miao Yu
- Department of Anorectal Surgery, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
| | - Yanfeng Lv
- Department of Anorectal Surgery, The Second Hospital of Shandong UniversityJinan 250033, Shandong Province, China
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Wang HP, Wang YY, Pan J, Cen R, Cai YK. Evaluation of specific fecal protein biochips for the diagnosis of colorectal cancer. World J Gastroenterol 2014; 20:1332-1339. [PMID: 24574808 PMCID: PMC3921516 DOI: 10.3748/wjg.v20.i5.1332] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2013] [Revised: 09/28/2013] [Accepted: 11/13/2013] [Indexed: 02/07/2023] Open
Abstract
AIM: To develop and initially test a potential fecal protein biochip for the screening of colorectal cancer (CRC).
METHODS: Fecal protein from 20 colorectal cancer patients and 20 healthy controls were extracted from all of the fecal samples and screened for proteomic differences using a Biotin label-based protein array. Candidate proteins were then verified by ELISA. Finally, we will select out the significant protein and a seven-target multiplex fecal protein biochip was generated and tested for 20 fecal samples to determine the effectiveness of the biochip on identifying CRC. And the value of the protein biochip would be discussed.
RESULTS: After tested by protein biochip of the fecal protein from 20 colorectal cancer patients and 20 healthy controls and levels of calprotectin, M2-pyruvatekinase, angiopoietin-2, fibroblast growth factor-23 (FGF-23), proteins of the matrix metalloproteinase, thrombopoietin (TPO) and interleukin-13 (IL-13) were significantly different between CRC and healthy controls. The sensitivity of all the seven proteins combined was 0.7, specificity was 0.4, and area under the receiver operating characteristics was 0.729. The most promising combinations of test proteins were FGF-23, TPO, and IL-13, reaching a sensitivity of 0.7 and a specificity of 0.7. The combination of FGF-23 and TPO scored highest with sensitivity of 0.7 and specificity of 0.8. Its mean that the combination of FGF-23 and TPO has the highest value for the diagnosis of CRC in our study.
CONCLUSION: A protein biochip composed of proteins found to be elevated in the feces of colorectal cancer patients has great potential as a noninvasive diagnostic for colorectal cancer. The addition of new protein biomarkers and technologies, as they are discovered, is an excellent avenue of future research.
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Maio GD, Rengucci C, Zoli W, Calistri D. Circulating and stool nucleic acid analysis for colorectal cancer diagnosis. World J Gastroenterol 2014; 20:957-67. [PMID: 24574768 PMCID: PMC3921547 DOI: 10.3748/wjg.v20.i4.957] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2013] [Revised: 12/05/2013] [Accepted: 01/06/2014] [Indexed: 02/06/2023] Open
Abstract
In recent years, the need to identify molecular markers characterized by high sensitivity and specificity in detecting and monitoring early and colorectal cancer lesions has increased. Up to now, none of the markers or panels of markers analyzed have met the rigorous standards required of a screening program. The important discovery of circulating nucleic acids in biological fluids has aroused intense scientific interest because of their usefulness in malignant and non malignant diseases. Over time, their yield and stability have been identified and compared with other "standard" biomarkers. The analysis of circulating DNA from blood and stool is a relatively simple and non-invasive procedure, representing a very attractive marker to detect genetic and epigenetic mutations and to monitor disease progression. A correlation between blood and stool biomarkers could also help to enhance currently available diagnostic approaches. However, various processing and analytic problems need to be resolved before such an approach can be applied in clinical practice.
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Sinagra E, Tomasello G, Raimondo D, Sturm A, Giunta M, Messina M, Damiano G, Palumbo VD, Spinelli G, Rossi F, Facella T, Marasà S, Cottone M, Lo Monte AI. Advanced endoscopic imaging for surveillance for dysplasia and colorectal cancer in inflammatory bowel disease: could the pathologist be further helped? Saudi J Gastroenterol 2014; 20:26-38. [PMID: 24496155 PMCID: PMC3952417 DOI: 10.4103/1319-3767.126314] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 11/03/2013] [Indexed: 12/18/2022] Open
Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal cancer. The magnitude of that increased risk as well as how best to mitigate it remain a topic of ongoing investigation in the field. It is important to quantify the risk of colorectal cancer in association with IBD. The reported risk varies widely between studies. This is partly due to the different methodologies used in the studies. Because of the limitations of surveillance strategies based on the detection of dysplasia, advanced endoscopic imaging and techniques involving the detection of alterations in mucosal antigens and genetic abnormalities are being investigated. Development of new biomarkers, predicting future occurrence of colonic neoplasia may lead to more biomarker-based surveillance. There are promising results that may lead to more efficient surveillance in IBD patients and more general acceptance of its use. A multidisciplinary approach, involving in particular endoscopists and pathologists, together with a centralized patient management, could help to optimize treatments and follow-up measures, both of which could help to reduce the IBD-associated cancer risk.
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Affiliation(s)
- Emanuele Sinagra
- PhD Course in Surgical Biotechnology and Regenerative Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
- Ospedale San Raffaele - Giglio, Gastroenterology and Endoscopy Unit, Cefalù, Italy
| | - Giovanni Tomasello
- DICHIRONS Department, School of Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
| | - Dario Raimondo
- Ospedale San Raffaele - Giglio, Gastroenterology and Endoscopy Unit, Cefalù, Italy
| | - Andreas Sturm
- Krankenhaus Waldfriede, Akademisches Lehrkrankenhaus DER Charite, Argentinische Allee 40, 14163 Berlin, Germany
| | - Marco Giunta
- Ospedali Riuniti Villa Sofia - Cervello, Unit of Gastroenterology, via Trabucco 180, 90146 Palermo, Italy
| | - Marco Messina
- Ospedale San Raffaele - Giglio, Unit of Oncology, Cefalù, Italy
| | - Giuseppe Damiano
- AOUP Paolo Giaccone, School of Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
| | - Vincenzo D. Palumbo
- AOUP Paolo Giaccone, School of Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
| | - Gabriele Spinelli
- AOUP Paolo Giaccone, School of Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
| | - Francesca Rossi
- Ospedale San Raffaele - Giglio, Gastroenterology and Endoscopy Unit, Cefalù, Italy
| | - Tiziana Facella
- Ospedale San Raffaele - Giglio, Gastroenterology and Endoscopy Unit, Cefalù, Italy
| | | | - Mario Cottone
- DIBIMIS Department, Ospedali Riuniti Villa Sofia - Cervello, Unit of Internal Medicine, via Trabucco 180, 90146 Palermo, Italy
| | - Attilio I. Lo Monte
- DICHIRONS Department, School of Medicine, University of Palermo, via Trabucco 180, 90146 Palermo, Italy
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Kahi CJ, Anderson JC, Rex DK. Screening and surveillance for colorectal cancer: state of the art. Gastrointest Endosc 2013; 77:335-50. [PMID: 23410695 DOI: 10.1016/j.gie.2013.01.002] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 01/01/2013] [Indexed: 12/11/2022]
Affiliation(s)
- Charles J Kahi
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN, USA
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Kanthan R, Senger JL, Kanthan SC. Molecular events in primary and metastatic colorectal carcinoma: a review. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:597497. [PMID: 22997602 PMCID: PMC3357597 DOI: 10.1155/2012/597497] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2011] [Accepted: 02/23/2012] [Indexed: 12/13/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease, developing through a multipathway sequence of events guided by clonal selections. Pathways included in the development of CRC may be broadly categorized into (a) genomic instability, including chromosomal instability (CIN), microsatellite instability (MSI), and CpG island methylator phenotype (CIMP), (b) genomic mutations including suppression of tumour suppressor genes and activation of tumour oncogenes, (c) microRNA, and (d) epigenetic changes. As cancer becomes more advanced, invasion and metastases are facilitated through the epithelial-mesenchymal transition (EMT), with additional genetic alterations. Despite ongoing identification of genetic and epigenetic markers and the understanding of alternative pathways involved in the development and progression of this disease, CRC remains the second highest cause of malignancy-related mortality in Canada. The molecular events that underlie the tumorigenesis of primary and metastatic colorectal carcinoma are detailed in this manuscript.
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Affiliation(s)
- Rani Kanthan
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W8
- Royal University Hospital, Room 2868 G-Wing, 103 Hospital Drive, Saskatoon, SK, Canada S7N 0W8
| | - Jenna-Lynn Senger
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon, SK, Canada S7N 0W8
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