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Alampritis G, Thoukididou SN, Ramos M, Georgiou P, Kalofonou M, Simillis C. Diagnostic value of genetic and epigenetic biomarker panels for colorectal cancer detection: a systematic review. Int J Colorectal Dis 2025; 40:125. [PMID: 40402271 PMCID: PMC12098509 DOI: 10.1007/s00384-025-04904-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/29/2025] [Indexed: 05/23/2025]
Abstract
PURPOSE Exploration of effective screening methods is imperative to improve current screening for colorectal cancer (CRC). Our aim was to systematically search the literature to identify and assess the diagnostic accuracy of both genetic and epigenetic biomarker panels for CRC detection using liquid biopsies for circulating tumour DNA (ctDNA) from stool, blood, or urine. METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) with searches in Medline, Embase, CENTRAL, and Web Of Science from inception up to March 20, 2025, using pre-defined keywords. Study quality assessment was performed using QUADAS-2 tool (Quality Assessment for Diagnostic Accuracy Studies 2). Primary and secondary outcomes were panel performance (sensitivity and specificity) for CRC, advanced precancerous lesions (APL), and staging of disease. RESULTS Forty-four studies were included. Exceptional performance for both CRC (sensitivity and specificity) and APL (sensitivity) was displayed by biomarker panels including methylated SDC2 with methylated SFRP1/2 (CRC: 91.5%/97.3%, APL: 89.2%) or methylated TFPI2 (CRC: 94.9%/98.1%, APL: 100%), and a 5-biomarker panel of mutational targets APC, Bat-26, KRAS, L-DNA, and p53 (CRC: 91.0%/93.0%, APL: 82.0%). Suboptimal APL sensitivities up to 57.0% were exhibited by Cologuard and variant panels (including KRAS, methylated BMP3, methylated NDRG4, FIT), and 47.8% for combinations including methylated SEPT9. CONCLUSIONS High-performance, candidate ctDNA biomarker panels with exceptional diagnostic accuracy for both CRC and APL have been identified. Further work should focus on the development of large-scale studies to justify their clinical implementation.
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Affiliation(s)
- Georgios Alampritis
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Sarah Nohelia Thoukididou
- Department of Surgery, University of Cambridge, Cambridge, UK
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Maria Ramos
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Pantelis Georgiou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Melpomeni Kalofonou
- Department of Electrical and Electronic Engineering, Imperial College London, London, UK
| | - Constantinos Simillis
- Department of Surgery, University of Cambridge, Cambridge, UK.
- Cambridge Colorectal Unit, Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
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Newell ME, Babbrah A, Aravindan A, Rathnam R, Halden RU. DNA Methylation in Urine and Feces Indicative of Eight Major Human Cancer Types Globally. Life (Basel) 2025; 15:482. [PMID: 40141826 PMCID: PMC11943902 DOI: 10.3390/life15030482] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 03/05/2025] [Accepted: 03/13/2025] [Indexed: 03/28/2025] Open
Abstract
Toxic chemicals and epigenetic biomarkers associated with cancer have been used successfully in clinical diagnostic screening of feces and urine from individuals, but they have been underutilized in a global setting. We analyzed peer-reviewed literature to achieve the following: (i) compile epigenetic biomarkers of disease, (ii) explore whether research locations are geographically aligned with disease hotspots, and (iii) determine the potential for tracking disease-associated epigenetic biomarkers. Studies (n = 1145) of epigenetic biomarkers (n = 146) in urine and feces from individuals have established notable diagnostic potential for detecting and tracking primarily gastric and urinary cancers. Panels with the highest sensitivity and specificity reported more than once were SEPT9 (78% and 93%, respectively) and the binary biomarker combinations GDF15, TMEFF2, and VIM (93% and 95%), NDRG4 and BMP3 (98% and 90%), and TWIST1 and NID2 (76% and 79%). Screening for epigenetic biomarkers has focused on biospecimens from the U.S., Europe, and East Asia, whereas data are limited in regions with similar/higher disease incidence rates (i.e., data for New Zealand, Japan, and Australia for colorectal cancer). The epigenetic markers discussed here may aid in the future monitoring of multiple cancers from individual- to population-level scales by leveraging the emerging science of wastewater-based epidemiology (WBE).
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Affiliation(s)
- Melanie Engstrom Newell
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
| | - Ayesha Babbrah
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Anumitha Aravindan
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Raj Rathnam
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
| | - Rolf U. Halden
- Biodesign Institute, Arizona State University, Tempe, AZ 85281, USA; (M.E.N.)
- Biodesign Center for Environmental Health Engineering, Tempe, AZ 85281, USA
- School for Engineering of Matter, Transport and Energy, Arizona State University, Tempe, AZ 85281, USA
- Barrett, The Honors College, Arizona State University, Tempe, AZ 85281, USA
- School of Sustainable Engineering and the Built Environment, Arizona State University, Tempe, AZ 85281, USA
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Partyka O, Pajewska M, Czerw A, Deptała A, Mękal D, Sygit K, Kowalczyk D, Cipora E, Kaczmarski M, Gazdowicz L, Dykowska G, Sienkiewicz Z, Banaś T, Małecki K, Grochans E, Grochans S, Cybulska AM, Schneider-Matyka D, Bandurska E, Bandurski T, Drobnik J, Pobrotyn P, Marczak M, Kozlowski R. Current Progress in Clinical Research in Secondary Prevention and Early Detection of Colorectal Cancer. Cancers (Basel) 2025; 17:367. [PMID: 39941735 PMCID: PMC11816288 DOI: 10.3390/cancers17030367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/08/2025] [Accepted: 01/20/2025] [Indexed: 02/16/2025] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally. The risk of disease increases with age, as most CRC patients are over 50 years old. Due to the progressive aging of societies in high-income countries, the problem of CRC will increase. This makes the development of new early detection methods and the implementation of effective screening programs crucial. Key areas of focus include raising population awareness about the importance of screening, educating high-risk populations, and improving and developing early diagnostic methods. The primary goal of this review is to provide a concise overview of recent trends and progress in CRC secondary prevention based on available information from clinical trials.
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Affiliation(s)
- Olga Partyka
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Monika Pajewska
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH—National Research Institute, 00-791 Warsaw, Poland
| | - Aleksandra Czerw
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland
- Department of Economic and System Analyses, National Institute of Public Health NIH—National Research Institute, 00-791 Warsaw, Poland
| | - Andrzej Deptała
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Dominika Mękal
- Department of Oncology Propaedeutics, Medical University of Warsaw, 01-445 Warsaw, Poland
| | - Katarzyna Sygit
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Dariusz Kowalczyk
- Faculty of Health Sciences, Calisia University, 62-800 Kalisz, Poland
| | - Elżbieta Cipora
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Mateusz Kaczmarski
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Lucyna Gazdowicz
- Medical Institute, Jan Grodek State University in Sanok, 38-500 Sanok, Poland
| | - Grażyna Dykowska
- Department of Health Economics and Medical Law, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Zofia Sienkiewicz
- Department of Nursing, Social and Medical Development, Medical University of Warsaw, 02-091 Warsaw, Poland
| | - Tomasz Banaś
- Department of Radiotherapy, Maria Sklodowska-Curie Institute-Oncology Centre, 31-115 Cracow, Poland
| | - Krzysztof Małecki
- Department of Radiotherapy for Children and Adults, University Children’s Hospital of Cracow, 30-663 Cracow, Poland
| | - Elżbieta Grochans
- Department of Nursing, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Szymon Grochans
- Department of Clinical Nursing, Faculty of Health Sciences, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Anna Maria Cybulska
- Department of Nursing, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Daria Schneider-Matyka
- Department of Nursing, Pomeranian Medical University in Szczecin, 71-210 Szczecin, Poland
| | - Ewa Bandurska
- Center for Competence Development, Integrated Care and e-Health, Medical University of Gdansk, 80-204 Gdansk, Poland
| | - Tomasz Bandurski
- Division of Radiology Informatics and Statistics, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Jarosław Drobnik
- Department of Family Medicine, Faculty of Medicine, Wroclaw Medical University, 51-141 Wroclaw, Poland
| | - Piotr Pobrotyn
- Remedial Specialistic Clinic, “Pulsantis Sp. z o.o”, 53-238 Wroclaw, Poland
| | - Michal Marczak
- Department of Innovation, Merito University in Poznan, 61-895 Poznan, Poland
| | - Remigiusz Kozlowski
- Department of Management and Logistics in Healthcare, Medical University of Lodz, 90-131 Lodz, Poland
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Mannucci A, Goel A. Stool and blood biomarkers for colorectal cancer management: an update on screening and disease monitoring. Mol Cancer 2024; 23:259. [PMID: 39558327 PMCID: PMC11575410 DOI: 10.1186/s12943-024-02174-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 11/07/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Biomarkers have revolutionized the management of colorectal cancer (CRC), facilitating early detection, prevention, personalized treatment, and minimal residual disease (MRD) monitoring. This review explores current CRC screening strategies and emerging biomarker applications. MAIN BODY We summarize the landscape of non-invasive CRC screening and MRD detection strategies, discuss the limitations of the current approaches, and highlight the promising potential of novel biomarker solutions. The fecal immunochemical test remained the cornerstone of CRC screening, but its sensitivity has been improved by assays that combined its performance with other stool analytes. However, their sensitivity for advanced adenomas and the patient compliance both remain suboptimal. Blood-based tests promise to increase compliance but require further refinement to compete with stool-based biomarker tests. The ideal scenario involves leveraging blood tests to increase screening participation, and simultaneously promote stool- and endoscopy-based screening among those who are compliant. Once solely reliant on upfront surgery followed by stage and pathology-driven adjuvant chemotherapy, the treatment of stage II and III colon cancer has undergone a revolutionary transformation with the advent of MRD testing after surgery. A decade ago, the concept of using a post-surgical test instead of stage and pathology to determine the need for adjuvant chemotherapy was disruptive. Today, a blood test may be more informative of the need for chemotherapy than the stage at diagnosis. CONCLUSION Biomarker research is not just improving, but bringing a transformative change to CRC clinical management. Early detection is not just getting better, but improving thanks to a multi-modality approach, and personalized treatment plans are not just becoming a reality, but a promising future with MRD testing.
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Affiliation(s)
- Alessandro Mannucci
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute at City of Hope, Monrovia, CA, USA
- Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Hospital, Milan, Italy
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute at City of Hope, Monrovia, CA, USA.
- City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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Liu Y, Ming H, Xu L, Li L, Liu Q, Zhao J, Zhong C, Li H. DNA methylation analysis of the SDC2, SEPT9 and VIM genes in fecal DNA for colorectal cancer diagnosis. BMC Cancer 2024; 24:1205. [PMID: 39350171 PMCID: PMC11440654 DOI: 10.1186/s12885-024-12990-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 09/24/2024] [Indexed: 10/04/2024] Open
Abstract
BACKGROUND Colorectal cancer is one of the most common cancers worldwide. DNA methylation sites may serve as a new gene signature for colorectal cancer diagnosis. The search for representative DNA methylation sites is urgently needed. This study aimed to systematically identify a methylation gene panel for colorectal cancer diagnosis via tissue and fecal samples. METHODS A total of 181 fecal and 50 tumor tissue samples were collected. They were obtained from 83 colorectal cancer patients and 98 healthy subjects. These samples were evaluated for DNA methylation of 9 target genes via quantitative bisulfite next-generation sequencing. We employed the rank-sum test to screen the colorectal cancer-specific methylation sites in the tissue and fecal cohorts. A data model was subsequently constructed and validated via the dedicated validation dataset. RESULTS Compared with the fecal and negative control samples, the colorectal cancer tissue samples presented significantly higher methylation rates for all the selected gene sites. The methylation rates of the tissue and preoperative fecal samples showed the same high and low rates at the same sites. After screening, a panel of 29 loci in the SDC2, SEPT9, and VIM genes proved to be reliable biomarkers for colorectal cancer diagnosis in fecal samples. Logistic regression models were then constructed and validated using this panel. The sensitivity of the model was 91.43% (95% CI = [89.69, 93.17]), the specificity was 100% (95% CI = [100,100]), and the AUC value is 99.31% (95% CI = [99,99.62]). The diagnostic accuracy of the model for stage I and stage II colorectal cancer was 100% (11/11) and 91.3% (21/23), respectively. Overall, this study confirms that the gene locus panel and the model can be used to diagnose colorectal cancer effectively through feces. CONCLUSIONS Our study identified a set of key methylation sites for colorectal cancer diagnosis from fecal samples, highlighting the importance of using tissue and fecal samples to accurately assess DNA methylation levels to screen for methylation sites, and developing an effective diagnostic model for colorectal cancer.
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Affiliation(s)
- Yue Liu
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Hongbo Ming
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Lizhi Xu
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Lizhen Li
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Qi Liu
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Jinyin Zhao
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China
| | - Cundi Zhong
- Department of Laboratory, The Second Affiliated Hospital of Dalian Medical University, 216 Zhongshan Street, Ganjingzi District, Dalian, Liaoning, 116031, China.
| | - Hongzhi Li
- Dalian Gentalker Biotech Co., Ltd., 9-2, Jinqi Road, Jinpu New District , Dalian, Liaoning, 116635, China.
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Cao Q, Tian Y, Deng Z, Yang F, Chen E. Epigenetic Alteration in Colorectal Cancer: Potential Diagnostic and Prognostic Implications. Int J Mol Sci 2024; 25:3358. [PMID: 38542332 PMCID: PMC10969857 DOI: 10.3390/ijms25063358] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/01/2024] [Accepted: 03/12/2024] [Indexed: 01/03/2025] Open
Abstract
Colorectal cancer (CRC), a prevalent malignant tumor of the digestive system, ranks as the third and second in global incidence and mortality, respectively, in 2020, with 1.93 million new cases (≈10% of all cancers). There are 940,000 deaths (≈9.4% of all cancers), and the incidence of CRC in younger patients (under 50 years of age) has become a new trend. The pathogenesis of CRC is primarily attributed to a series of genetic and epigenetic abnormalities within normal colonic epithelial cells, coupled with the reshaping of the tumor microenvironment in the surrounding stroma. This process leads to the transformation of colorectal adenomas into invasive adenocarcinomas. Although genetic changes are known to be the primary driving force in the occurrence and progression of CRC, recent research indicates that epigenetic regulation serves as a crucial molecular marker in cancer, playing a significant role in the pathological and physiological control of interactions between genetics and the environment. This review discusses the current global epidemiology of CRC, its risk factors, and preventive treatment strategies. The current study explores the latest advancements in the epigenetic regulation of CRC, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs). These developments hold potential as screening tools, prognostic biomarkers, and therapeutic targets for CRC.
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Affiliation(s)
- Qing Cao
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Ye Tian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Zhiyi Deng
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Fangfang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
| | - Erfei Chen
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Northwest University, Xi’an 710069, China; (Q.C.); (Y.T.); (Z.D.); (F.Y.)
- Provincial Key Laboratory of Biotechnology of Shaanxi Province, Northwest University, Xi’an 710069, China
- School of Medicine, Northwest University, Xi’an 710069, China
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Mokhtari K, Peymani M, Rashidi M, Hushmandi K, Ghaedi K, Taheriazam A, Hashemi M. Colon cancer transcriptome. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2023; 180-181:49-82. [PMID: 37059270 DOI: 10.1016/j.pbiomolbio.2023.04.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 03/31/2023] [Accepted: 04/06/2023] [Indexed: 04/16/2023]
Abstract
Over the last four decades, methodological innovations have continuously changed transcriptome profiling. It is now feasible to sequence and quantify the transcriptional outputs of individual cells or thousands of samples using RNA sequencing (RNA-seq). These transcriptomes serve as a connection between cellular behaviors and their underlying molecular mechanisms, such as mutations. This relationship, in the context of cancer, provides a chance to unravel tumor complexity and heterogeneity and uncover novel biomarkers or treatment options. Since colon cancer is one of the most frequent malignancies, its prognosis and diagnosis seem to be critical. The transcriptome technology is developing for an earlier and more accurate diagnosis of cancer which can provide better protectivity and prognostic utility to medical teams and patients. A transcriptome is a whole set of expressed coding and non-coding RNAs in an individual or cell population. The cancer transcriptome includes RNA-based changes. The combined genome and transcriptome of a patient may provide a comprehensive picture of their cancer, and this information is beginning to affect treatment decision-making in real-time. A full assessment of the transcriptome of colon (colorectal) cancer has been assessed in this review paper based on risk factors such as age, obesity, gender, alcohol use, race, and also different stages of cancer, as well as non-coding RNAs like circRNAs, miRNAs, lncRNAs, and siRNAs. Similarly, they have been examined independently in the transcriptome study of colon cancer.
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Affiliation(s)
- Khatere Mokhtari
- Department of Modern Biology, ACECR Institute of Higher Education (Isfahan Branch), Isfahan, Iran
| | - Maryam Peymani
- Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, 4815733971, Iran
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran
| | - Kamran Ghaedi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran.
| | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Zhang X, Hou H, Jiang M, Zhang X. Aberrant circulating tumor DNA methylation and exosomal microRNA biomarkers for early detection of colorectal cancer. Mol Biol Rep 2023; 50:2743-2750. [PMID: 36583782 DOI: 10.1007/s11033-022-08194-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Accepted: 12/06/2022] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) became the third most commonly diagnosed malignancy and the second leading cause of cancer death in 2020. However, the rates of early screening and early diagnosis for CRC remain unsatisfactory. Thus, it is essential to explore the initiating factors of CRC and strategies for its early diagnosis. Research progress in liquid biopsy has led to the finding that circulating tumor-derived DNA (ctDNA) and exosomes play vital roles in early detection of CRC. THE APPLICATIONS OF LIQUID BIOPSY FOR EARLY DETECTION OF COLORECTAL CANCER: Moreover, the increased understanding of epigenetics has highlighted the role of ctDNA methylation in CRC carcinogenesis, and the detection of aberrant ctDNA methylation markers is a feasible strategy for diagnosis of early-stage CRC. Among exosomal markers, microRNAs (miRNAs) are abundant and are the most researched. Upregulated or downregulated expression of exosome-derived miRNAs can indicate the occurrence of early-stage CRC. FUTURE PERSPECTIVE The current research progress on aberrant ctDNA methylation and tumor exosomal miRNA biomarkers in early detection of CRC is summarized in this review, and the advantages and shortcomings of the methods are discussed.
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Affiliation(s)
- Xuchen Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Cancer Institute, Qingdao University, Qingdao, China
| | - Helei Hou
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Cancer Institute, Qingdao University, Qingdao, China
| | - Man Jiang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.,Qingdao Cancer Institute, Qingdao University, Qingdao, China
| | - Xiaochun Zhang
- Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China. .,Qingdao Cancer Institute, Qingdao University, Qingdao, China.
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Chu DT, Ngo AD, Wu CC. Epigenetics in cancer development, diagnosis and therapy. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 198:73-92. [PMID: 37225325 DOI: 10.1016/bs.pmbts.2023.01.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
Cancer is a dangerous disease and one of the leading causes of death in the world. In 2020, there were nearly 10 million cancer deaths and approximately 20 million new cases. New cases and deaths from cancer are expected to increase further in the coming years. To have a deeper insight into the mechanism of carcinogenesis, epigenetics studies have been published and received much attention from scientists, doctors, and patients. Among alterations in epigenetics, DNA methylation and histone modification are studied by many scientists. They have been reported to be a major contributor in tumor formation and are involved in metastasis. From the understanding of DNA methylation and histone modification, effective, accurate and cost-effective methods for diagnosis and screening of cancer patients have been introduced. Furthermore, therapeutic approaches and drugs targeting altered epigenetics have also been clinically studied and have shown positive results in combating tumor progression. Several cancer drugs that rely on DNA methylation inactivation or histone modification have been approved by the FDA for the treatment of cancer patients. In summary, epigenetics changes such as DNA methylation or histone modification are take part in tumor growth, and they also have great prospect to study diagnostic and therapeutic methods of this dangerous disease.
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Affiliation(s)
- Dinh-Toi Chu
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam; Faculty of Applied Sciences, International School, Vietnam National University, Hanoi, Vietnam.
| | - Anh-Dao Ngo
- Center for Biomedicine and Community Health, International School, Vietnam National University, Hanoi, Vietnam
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan; International Center for Wound Repair and Regeneration, National Cheng Kung University, Tainan, Taiwan; Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
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Ko B, Hanna M, Yu M, Grady WM. Epigenetic Alterations in Colorectal Cancer. EPIGENETICS AND HUMAN HEALTH 2023:331-361. [DOI: 10.1007/978-3-031-42365-9_10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Ghavami S, Zamani M, Ahmadi M, Erfani M, Dastghaib S, Darbandi M, Darbandi S, Vakili O, Siri M, Grabarek BO, Boroń D, Zarghooni M, Wiechec E, Mokarram P. Epigenetic regulation of autophagy in gastrointestinal cancers. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166512. [PMID: 35931405 DOI: 10.1016/j.bbadis.2022.166512] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/09/2022]
Abstract
The development of novel therapeutic approaches is necessary to manage gastrointestinal cancers (GICs). Considering the effective molecular mechanisms involved in tumor growth, the therapeutic response is pivotal in this process. Autophagy is a highly conserved catabolic process that acts as a double-edged sword in tumorigenesis and tumor inhibition in a context-dependent manner. Depending on the stage of malignancy and cellular origin of the tumor, autophagy might result in cancer cell survival or death during the GICs' progression. Moreover, autophagy can prevent the progression of GIC in the early stages but leads to chemoresistance in advanced stages. Therefore, targeting specific arms of autophagy could be a promising strategy in the prevention of chemoresistance and treatment of GIC. It has been revealed that autophagy is a cytoplasmic event that is subject to transcriptional and epigenetic regulation inside the nucleus. The effect of epigenetic regulation (including DNA methylation, histone modification, and expression of non-coding RNAs (ncRNAs) in cellular fate is still not completely understood. Recent findings have indicated that epigenetic alterations can modify several genes and modulators, eventually leading to inhibition or promotion of autophagy in different cancer stages, and mediating chemoresistance or chemosensitivity. The current review focuses on the links between autophagy and epigenetics in GICs and discusses: 1) How autophagy and epigenetics are linked in GICs, by considering different epigenetic mechanisms; 2) how epigenetics may be involved in the alteration of cancer-related phenotypes, including cell proliferation, invasion, and migration; and 3) how epidrugs modulate autophagy in GICs to overcome chemoresistance.
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Affiliation(s)
- Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada; Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland.
| | - Mozhdeh Zamani
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mazaher Ahmadi
- Department of Analytical Chemistry, Faculty of Chemistry, Bu-Ali Sina University, Hamedan, Iran
| | - Mehran Erfani
- Department of Biochemistry, School of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Sanaz Dastghaib
- Endocrinology and Metabolism Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mahsa Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Sara Darbandi
- Fetal Health Research Center, Hope Generation Foundation, Tehran, Iran; Gene Therapy and Regenerative Medicine Research Center, Hope Generation Foundation, Tehran, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Morvarid Siri
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Beniamin Oskar Grabarek
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Dariusz Boroń
- Department of Histology, Cytophysiology, and Embryology in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland; Department of Gynecology and Obstetrics in Zabrze, Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
| | - Maryam Zarghooni
- Department of Laboratory Medicine and Pathobiology, University of Toronto Alumni, Toronto, Canada
| | - Emilia Wiechec
- Division of Cell Biology, Department of Biomedical and Clinical Sciences, Linköping University, 58185 Linköping, Sweden
| | - Pooneh Mokarram
- Autophagy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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12
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Massen M, Lommen K, Wouters KAD, Vandersmissen J, van Criekinge W, Herman JG, Melotte V, Schouten LJ, van Engeland M, Smits KM. Technical considerations in PCR-based assay design for diagnostic DNA methylation cancer biomarkers. Clin Epigenetics 2022; 14:56. [PMID: 35477541 PMCID: PMC9047347 DOI: 10.1186/s13148-022-01273-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 04/07/2022] [Indexed: 11/21/2022] Open
Abstract
Background DNA methylation biomarkers for early detection, risk stratification and treatment response in cancer have been of great interest over the past decades. Nevertheless, clinical implementation of these biomarkers is limited, as only < 1% of the identified biomarkers is translated into a clinical or commercial setting. Technical factors such as a suboptimal genomic location of the assay and inefficient primer or probe design have been emphasized as important pitfalls in biomarker research. Here, we use eleven diagnostic DNA methylation biomarkers for colorectal cancer (ALX4, APC, CDKN2A, MGMT, MLH1, NDRG4, SDC2, SFRP1, SFRP2, TFPI1 and VIM), previously described in a systematic literature search, to evaluate these pitfalls. Results To assess the genomic assay location, the optimal genomic locations according to TCGA data were extracted and compared to the genomic locations used in the published assays for all eleven biomarkers. In addition, all primers and probes were technically evaluated according to several criteria, based on literature and expert opinion. Both assay location and assay design quality varied widely among studies. Conclusions Large variation in both assay location and design hinders the development of future DNA methylation biomarkers as well as inter-study comparability.
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Affiliation(s)
- Maartje Massen
- Department of Pathology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Kim Lommen
- Department of Pathology, GROW - School for Oncology and Reproduction, 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 Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | | | - Wim van Criekinge
- Department of Mathematical Modelling, Statistics and Bioinformatics, Ghent University, 9000, Ghent, Belgium
| | - James G Herman
- The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15232, USA
| | - Veerle Melotte
- Department of Pathology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.,Department of Clinical Genetics, Erasmus University Medical Center, 3015 GD, Rotterdam, The Netherlands
| | - Leo J Schouten
- Department of Epidemiology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Manon van Engeland
- Department of Pathology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands
| | - Kim M Smits
- Department of Pathology, GROW - School for Oncology and Reproduction, Maastricht University Medical Center, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
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13
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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14
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Beltrán-García J, Osca-Verdegal R, Mena-Mollá S, Seco-Cervera M, Peiró-Chova L, García-Giménez JL, Laurent-Puig P, Cervantes A. Translational epigenetics in precision medicine of colorectal cancer. EPIGENETICS IN PRECISION MEDICINE 2022:19-41. [DOI: 10.1016/b978-0-12-823008-4.00018-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Almeida-Lousada H, Mestre A, Ramalhete S, Price AJ, de Mello RA, Marreiros AD, Neves RPD, Castelo-Branco P. Screening for Colorectal Cancer Leading into a New Decade: The "Roaring '20s" for Epigenetic Biomarkers? Curr Oncol 2021; 28:4874-4893. [PMID: 34898591 PMCID: PMC8628779 DOI: 10.3390/curroncol28060411] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) has an important bearing (top five) on cancer incidence and mortality in the world. The etiology of sporadic CRC is related to the accumulation of genetic and epigenetic alterations that result in the appearance of cancer hallmarks such as abnormal proliferation, evasion of immune destruction, resistance to apoptosis, replicative immortality, and others, contributing to cancer promotion, invasion, and metastasis. It is estimated that, each year, at least four million people are diagnosed with CRC in the world. Depending on CRC staging at diagnosis, many of these patients die, as CRC is in the top four causes of cancer death in the world. New and improved screening tests for CRC are needed to detect the disease at an early stage and adopt patient management strategies to decrease the death toll. The three pillars of CRC screening are endoscopy, radiological imaging, and molecular assays. Endoscopic procedures comprise traditional colonoscopy, and more recently, capsule-based endoscopy. The main imaging modality remains Computed Tomography (CT) of the colon. Molecular approaches continue to grow in the diversity of biomarkers and the sophistication of the technologies deployed to detect them. What started with simple fecal occult blood tests has expanded to an armamentarium, including mutation detection and identification of aberrant epigenetic signatures known to be oncogenic. Biomarker-based screening methods have critical advantages and are likely to eclipse the classical modalities of imaging and endoscopy in the future. For example, imaging methods are costly and require highly specialized medical personnel. In the case of endoscopy, their invasiveness limits compliance from large swaths of the population, especially those with average CRC risk. Beyond mere discomfort and fear, there are legitimate iatrogenic concerns associated with endoscopy. The risks of perforation and infection make endoscopy best suited for a confirmatory role in cases where there are positive results from other diagnostic tests. Biomarker-based screening methods are largely non-invasive and are growing in scope. Epigenetic biomarkers, in particular, can be detected in feces and blood, are less invasive to the average-risk patient, detect early-stage CRC, and have a demonstrably superior patient follow-up. Given the heterogeneity of CRC as it evolves, optimal screening may require a battery of blood and stool tests, where each can leverage different pathways perturbed during carcinogenesis. What follows is a comprehensive, systematic review of the literature pertaining to the screening and diagnostic protocols used in CRC. Relevant articles were retrieved from the PubMed database using keywords including: "Screening", "Diagnosis", and "Biomarkers for CRC". American and European clinical trials in progress were included as well.
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Affiliation(s)
- Hélder Almeida-Lousada
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - André Mestre
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Sara Ramalhete
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Aryeh J. Price
- School of Law, University of California, Berkeley, CA 94704, USA;
| | - Ramon Andrade de Mello
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
- Precision Oncology & Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil
| | - Ana D. Marreiros
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Ricardo Pires das Neves
- CNC—Center for Neuroscience and Cell Biology, CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517 Coimbra, Portugal
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3004-517 Coimbra, Portugal
| | - Pedro Castelo-Branco
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
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16
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Detection of average methylation level of specific genes by binary-probe hybridization. Talanta 2021; 234:122630. [PMID: 34364439 DOI: 10.1016/j.talanta.2021.122630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2021] [Revised: 05/24/2021] [Accepted: 06/17/2021] [Indexed: 01/13/2023]
Abstract
We developed a simple and highly-selective method for 5-methylcytosine detection of specific gene sequence based on binary-probe DNA hybridization. The sequence complementary to the target was designed into two probes, and each fragment of binary probes bound to a relatively short sequence of the target, which made it sensitive to the base mismatches introduced by bisulfite treatment. The advantages of a low detection limit of methylation abundance of 0.1% for the fully methylated target and high sensitivity of 10 pM have been proved by the successful design of binary-probe hybridization. The successful design of the binary probes makes it possible to quantify the average methylation levels of five CpG sites. Thirty-two DNA strands containing 5, 4, 3, 2, 1 and 0 CpG sites were successfully analyzed with the same pair of binary probes. The higher the average methylation level of the target was, the higher the degree of the hybridization reaction. Based on the simple construction of the binary-probe hybridization, the developed biosensor exhibited signals proportional to the average methylation level of the vimentin gene and could evaluate the average methylation level of artificial mixtures. Furthermore, the method has been used to detect vimentin methylation in a genomic context with good specificity, which indicated its potential in the pre-diagnosis of methylation related disease.
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17
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Shafiei M, Alemrajabi M, Najafi A, Keihan AH, Sohrabi MR. Candidate Molecular Biomarkers for the Non- Invasive Detection of Colorectal Cancer using Gene Expression Profiling. IRANIAN JOURNAL OF PATHOLOGY 2021; 16:205-214. [PMID: 33936232 PMCID: PMC8085285 DOI: 10.30699/ijp.2021.132385.2475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 02/17/2021] [Indexed: 11/07/2022]
Abstract
Background & Objective: olorectal Cancer (CRC) is the third most common cancer after prostate (breast in women) and lung cancer; it is also the third cause of cancer deaths reported in both men and women in 2020. Currently, the most commonly used diagnostic tools for CRC are colonoscopy, serological methods, and other imaging techniques. Despite the benefits and abilities of these methods, each of them has disadvantages that reduce its functionality and acceptance. The aim of this study was identifying specific and non-invasive genetic biomarkers to diagnose colorectal cancer. Methods: In this study, changes in the expression of HLTF and SEPT9 genes were evaluated by Real Time PCR in blood and tissue samples of CRC patients. A total of 100 samples (50 Blood and 50 Tissue samples) were evaluated with a definite diagnosis of CRC in Firoozgar Hspital, Tehran, Iran, in 2018. The QPCR method was used to compare the expression of candidate genes between the patients group and control group in both samples. Sensitivity and specificity of the test were examined using ROC curve analysis. Results: The results showed a significant down-regulation in the expression of both selected genes in tissue and peripheral blood in the various stages of the CRC. The sensitivity and specifity of both genes was about 80%. Conclusion: The findings showed that the two candidate genes can be suggested as specific biomarkers for diagnosis of CRC using the peripheral blood as a non-invasive method. For a definite conclusion, more research is needed.
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Affiliation(s)
- Mohammad Shafiei
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mahdi Alemrajabi
- Gastrointestinal and Liver Disease Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Najafi
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Amir Homayoun Keihan
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Masoud Reza Sohrabi
- Gastrointestinal and Liver Disease Research Center (GILDRC), Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
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18
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Gachabayov M, Lebovics E, Rojas A, Felsenreich DM, Latifi R, Bergamaschi R. Performance evaluation of stool DNA methylation tests in colorectal cancer screening: a systematic review and meta-analysis. Colorectal Dis 2021; 23:1030-1042. [PMID: 33410272 DOI: 10.1111/codi.15521] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/30/2020] [Accepted: 12/30/2020] [Indexed: 12/16/2022]
Abstract
AIM There is not sufficient evidence about whether stool DNA methylation tests allow prioritizing patients to colonoscopy. Due to the COVID-19 pandemic, there will be a wait-list for rescheduling colonoscopies once the mitigation is lifted. The aim of this meta-analysis was to evaluate the accuracy of stool DNA methylation tests in detecting colorectal cancer. METHODS The PubMed, Cochrane Library and MEDLINE via Ovid were searched. Studies reporting the accuracy (Sackett phase 2 or 3) of stool DNA methylation tests to detect sporadic colorectal cancer were included. The DerSimonian-Laird method with random-effects model was utilized for meta-analysis. RESULTS Forty-six studies totaling 16 149 patients were included in the meta-analysis. The pooled sensitivity and specificity of all single genes and combinations was 62.7% (57.7%, 67.4%) and 91% (89.5%, 92.2%), respectively. Combinations of genes provided higher sensitivity compared to single genes (80.8% [75.1%, 85.4%] vs. 57.8% [52.3%, 63.1%]) with no significant decrease in specificity (87.8% [84.1%, 90.7%] vs. 92.1% [90.4%, 93.5%]). The most accurate single gene was found to be SDC2 with a sensitivity of 83.1% (72.6%, 90.2%) and a specificity of 91.2% (88.6%, 93.2%). CONCLUSIONS Stool DNA methylation tests have high specificity (92%) with relatively lower sensitivity (81%). Combining genes increases sensitivity compared to single gene tests. The single most accurate gene is SDC2, which should be considered for further research.
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Affiliation(s)
- Mahir Gachabayov
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Edward Lebovics
- Section of Gastroenterology, Department of Medicine, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Aram Rojas
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Daniel M Felsenreich
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Rifat Latifi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
| | - Roberto Bergamaschi
- Section of Colorectal Surgery, Department of Surgery, Westchester Medical Center, New York Medical College, Valhalla, NY, USA
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19
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Ruiz-Bañobre J, Goel A. Genomic and epigenomic biomarkers in colorectal cancer: From diagnosis to therapy. Adv Cancer Res 2021; 151:231-304. [PMID: 34148615 PMCID: PMC10338180 DOI: 10.1016/bs.acr.2021.02.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States. Despite ongoing efforts aimed at increasing screening for CRC and early detection, and development of more effective therapeutic regimens, the overall morbidity and mortality from this malignancy remains a clinical challenge. Therefore, identifying and developing genomic and epigenomic biomarkers that can improve CRC diagnosis and help predict response to current therapies are of paramount importance for improving survival outcomes in CRC patients, sparing patients from toxicity associated with current regimens, and reducing the economic burden associated with these treatments. Although efforts to develop biomarkers over the past decades have achieved some success, the recent availability of high-throughput analytical tools, together with the use of machine learning algorithms, will likely hasten the development of more robust diagnostic biomarkers and improved guidance for clinical decision-making in the coming years. In this chapter, we provide a systematic and comprehensive overview on the current status of genomic and epigenomic biomarkers in CRC, and comment on their potential clinical significance in the management of patients with this fatal malignancy, including in the context of precision medicine.
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Affiliation(s)
- Juan Ruiz-Bañobre
- Medical Oncology Department, University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain; Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), CIBERONC, Santiago de Compostela, Spain
| | - Ajay Goel
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, United States.
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20
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Grady WM. Epigenetic alterations in the gastrointestinal tract: Current and emerging use for biomarkers of cancer. Adv Cancer Res 2021; 151:425-468. [PMID: 34148620 DOI: 10.1016/bs.acr.2021.02.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Colorectal cancer is a leading cause of cancer related deaths worldwide. One of the hallmarks of cancer and a fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological process of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the initiation and progression of cancers, including colorectal cancer. Epigenetic alterations, which include changes affecting DNA methylation, histone modifications, chromatin structure, and noncoding RNA expression, have emerged as a major class of molecular alteration in colon polyps and colorectal cancer. The classes of epigenetic alterations, their status in colorectal polyps and cancer, their effects on neoplasm biology, and their application to clinical care will be discussed.
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Affiliation(s)
- William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States; Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA, United States.
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21
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Rodriguez-Casanova A, Costa-Fraga N, Bao-Caamano A, López-López R, Muinelo-Romay L, Diaz-Lagares A. Epigenetic Landscape of Liquid Biopsy in Colorectal Cancer. Front Cell Dev Biol 2021; 9:622459. [PMID: 33614651 PMCID: PMC7892964 DOI: 10.3389/fcell.2021.622459] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 01/05/2021] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignancies and is a major cause of cancer-related deaths worldwide. Thus, there is a clinical need to improve early detection of CRC and personalize therapy for patients with this disease. In the era of precision oncology, liquid biopsy has emerged as a major approach to characterize the circulating tumor elements present in body fluids, including cell-free DNA and RNA, circulating tumor cells, and extracellular vesicles. This non-invasive tool has allowed the identification of relevant molecular alterations in CRC patients, including some indicating the disruption of epigenetic mechanisms. Epigenetic alterations found in solid and liquid biopsies have shown great utility as biomarkers for early detection, prognosis, monitoring, and evaluation of therapeutic response in CRC patients. Here, we summarize current knowledge of the most relevant epigenetic mechanisms associated with cancer development and progression, and the implications of their deregulation in cancer cells and liquid biopsy of CRC patients. In particular, we describe the methodologies used to analyze these epigenetic alterations in circulating tumor material, and we focus on the clinical utility of epigenetic marks in liquid biopsy as tumor biomarkers for CRC patients. We also discuss the great challenges and emerging opportunities of this field for the diagnosis and personalized management of CRC patients.
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Affiliation(s)
- Aitor Rodriguez-Casanova
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain
| | - Nicolás Costa-Fraga
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Aida Bao-Caamano
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Rafael López-López
- Roche-Chus Joint Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), Santiago de Compostela, Spain.,Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
| | - Laura Muinelo-Romay
- Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain.,Liquid Biopsy Analysis Unit, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain
| | - Angel Diaz-Lagares
- Cancer Epigenomics Laboratory, Translational Medical Oncology Group (Oncomet), Health Research Institute of Santiago (IDIS), University Clinical Hospital of Santiago (CHUS/SERGAS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red Cáncer (CIBERONC), Madrid, Spain
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22
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Laugsand EA, Brenne SS, Skorpen F. DNA methylation markers detected in blood, stool, urine, and tissue in colorectal cancer: a systematic review of paired samples. Int J Colorectal Dis 2021; 36:239-251. [PMID: 33030559 PMCID: PMC7801356 DOI: 10.1007/s00384-020-03757-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/17/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Methylated cell-free DNA in liquid biopsies are promising non-invasive biomarkers for colorectal cancer (CRC). Optimal markers would have high sensitivity and specificity for early detection of CRC and could be detected in more than one type of material from the patient. We systematically reviewed the literature on DNA methylation markers of colorectal cancer, detected in more than one type of material, regarding their potential as contributors to a panel for screening and follow-up of CRC. METHODS The databases MEDLINE, Web of Science, and Embase were systematically searched. Data extraction and review was performed by two authors independently. Agreement between methylation status in tissue and other materials (blood/stool/urine) was analyzed using the McNemar test and Cohen's kappa. RESULTS From the 51 included studies, we identified seven single markers with sensitivity ≥ 75% and specificity ≥ 90% for CRC. We also identified one promising plasma panel and two stool panels. The correspondence of methylation status was evaluated as very good for four markers, but only marginal for most of the other markers investigated (12 of 21). CONCLUSION The included studies reported only some of the variables and markers of interest and included few patients. Hence, a meta-analysis was not possible at this point. Larger, prospective studies must be designed to study the discordant detection of markers in tissue and liquid biopsies. When reporting their findings, such studies should use a standardized format.
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Affiliation(s)
- Eivor Alette Laugsand
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway.
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway.
| | - Siv Sellæg Brenne
- Department of Surgery, Levanger Hospital, Nord-Trøndelag Hospital trust, N-7600, Levanger, Norway
- Department of Public Health and Nursing, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
| | - Frank Skorpen
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), N-7491, Trondheim, Norway
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23
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Grady WM, Yu M, Markowitz SD. Epigenetic Alterations in the Gastrointestinal Tract: Current and Emerging Use for Biomarkers of Cancer. Gastroenterology 2021; 160:690-709. [PMID: 33279516 PMCID: PMC7878343 DOI: 10.1053/j.gastro.2020.09.058] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 09/24/2020] [Accepted: 09/28/2020] [Indexed: 02/06/2023]
Abstract
Colorectal cancer, liver cancer, stomach cancer, pancreatic cancer, and esophageal cancer are leading causes of cancer-related deaths worldwide. A fundamental trait of virtually all gastrointestinal cancers is genomic and epigenomic DNA alterations. Cancer cells acquire genetic and epigenetic alterations that drive the initiation and progression of the cancers by altering the molecular and cell biological processes of the cells. These alterations, as well as other host and microenvironment factors, ultimately mediate the clinical behavior of the precancers and cancers and can be used as biomarkers for cancer risk determination, early detection of cancer and precancer, determination of the prognosis of cancer and prediction of the response to therapy. Epigenetic alterations have emerged as one of most robust classes of biomarkers and are the basis for a growing number of clinical tests for cancer screening and surveillance.
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Affiliation(s)
- William M. Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA,Division of Gastroenterology, University of Washington School of Medicine, Seattle, WA 98195, USA
| | - Ming Yu
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA
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24
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Cao Y, Zhao G, Yuan M, Liu X, Ma Y, Cao Y, Miao B, Zhao S, Li D, Xiong S, Zheng M, Fei S. KCNQ5 and C9orf50 Methylation in Stool DNA for Early Detection of Colorectal Cancer. Front Oncol 2021; 10:621295. [PMID: 33585248 PMCID: PMC7878552 DOI: 10.3389/fonc.2020.621295] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 12/14/2020] [Indexed: 12/24/2022] Open
Abstract
Background Aberrant DNA methylation has emerged as a class of promising biomarkers for early colorectal cancer (CRC) detection, but the performance of methylated C9orf50 and methylated KCNQ5 in stool DNA has never been evaluated. Methods Methylation specific quantitative PCR (qPCR) assays for methylated C9orf50 and methylated KCNQ5 were developed. The methylation levels of C9orf50 and KCNQ5 in 198 CRC patients, 20 advanced adenoma (AA) patients, 101 small polyp (SP) patients, and 141 no evidence of disease (NED) subjects were analyzed. Results The methylation levels of both KCNQ5 and C9orf50 genes were significantly higher in CRC and AA groups than those in SP and NED groups, but showed no significant difference among different stages of CRC. The sensitivities of methylated KCNQ5 and methylated C9orf50 for CRC detection were 77.3% (95% CI: 70.7–82.8%) and 85.9% (95% CI: 80.0–90.2%) with specificities of 91.5% (95% CI: 85.3–95.3%) and 95.0% (95% CI: 89.7–97.8%), respectively. When C9orf50 and methylated KCNQ5 were combined, the clinical performance for CRC detection was similar to that of methylated C9orf50 alone. Conclusions Stool DNA based methylated C9orf50 test has the potential to become an alternative approach for CRC screening and prevention.
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Affiliation(s)
- Yaping Cao
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Guodong Zhao
- Zhejiang University Kunshan Biotechnology Laboratory, Zhejiang University Kunshan Innovation Institute, Kunshan, China.,State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.,Department of R&D, Suzhou VersaBio Technologies Co. Ltd., Kunshan, China
| | - Mufa Yuan
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Xiaoyu Liu
- Zhejiang University Kunshan Biotechnology Laboratory, Zhejiang University Kunshan Innovation Institute, Kunshan, China
| | - Yong Ma
- Zhejiang University Kunshan Biotechnology Laboratory, Zhejiang University Kunshan Innovation Institute, Kunshan, China.,Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Yang Cao
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Bei Miao
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Shuyan Zhao
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Danning Li
- Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
| | - Shangmin Xiong
- Zhejiang University Kunshan Biotechnology Laboratory, Zhejiang University Kunshan Innovation Institute, Kunshan, China.,Department of R&D, Suzhou VersaBio Technologies Co. Ltd., Kunshan, China
| | - Minxue Zheng
- Zhejiang University Kunshan Biotechnology Laboratory, Zhejiang University Kunshan Innovation Institute, Kunshan, China.,Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, Suzhou, China
| | - Sujuan Fei
- Department of Gastroenterology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.,Institute of Digestive Diseases, Xuzhou Medical University, Xuzhou, China
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25
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Jung G, Hernández-Illán E, Moreira L, Balaguer F, Goel A. Epigenetics of colorectal cancer: biomarker and therapeutic potential. Nat Rev Gastroenterol Hepatol 2020; 17:111-130. [PMID: 31900466 PMCID: PMC7228650 DOI: 10.1038/s41575-019-0230-y] [Citation(s) in RCA: 504] [Impact Index Per Article: 100.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/16/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC), a leading cause of cancer-related death worldwide, evolves as a result of the stepwise accumulation of a series of genetic and epigenetic alterations in the normal colonic epithelium, leading to the development of colorectal adenomas and invasive adenocarcinomas. Although genetic alterations have a major role in a subset of CRCs, the pathophysiological contribution of epigenetic aberrations in this malignancy has attracted considerable attention. Data from the past couple of decades has unequivocally illustrated that epigenetic marks are important molecular hallmarks of cancer, as they occur very early in disease pathogenesis, involve virtually all key cancer-associated pathways and, most importantly, can be exploited as clinically relevant disease biomarkers for diagnosis, prognostication and prediction of treatment response. In this Review, we summarize the current knowledge on the best-studied epigenetic modifications in CRC, including DNA methylation and histone modifications, as well as the role of non-coding RNAs as epigenetic regulators. We focus on the emerging potential for the bench-to-bedside translation of some of these epigenetic alterations into clinical practice and discuss the burgeoning evidence supporting the potential of emerging epigenetic therapies in CRC as we usher in the era of precision medicine.
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Affiliation(s)
- Gerhard Jung
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Eva Hernández-Illán
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Leticia Moreira
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain.
| | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, USA.
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
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26
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Moradi Sarabi M, Mohammadrezaei Khorramabadi R, Zare Z, Eftekhar E. Polyunsaturated fatty acids and DNA methylation in colorectal cancer. World J Clin Cases 2019; 7:4172-4185. [PMID: 31911898 PMCID: PMC6940323 DOI: 10.12998/wjcc.v7.i24.4172] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/27/2019] [Accepted: 12/13/2019] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) has been designated a major global problem, especially due to its high prevalence in developed countries. CRC mostly occurs sporadically (75%-80%), and only 20%-25% of patients have a family history. Several processes are involved in the development of CRC such as a combination of genetic and epigenetic alterations. Epigenetic changes, including DNA methylation play a vital role in the progression of CRC. Complex interactions between susceptibility genes and environmental factors, such as a diet and sedentary lifestyle, lead to the development of CRC. Clinical and experimental studies have confirmed the beneficial effects of dietary polyunsaturated fatty acids (PUFAs) in preventing CRC. From a mechanistic viewpoint, it has been suggested that PUFAs are pleiotropic agents that alter chromatin remodeling, membrane structure and downstream cell signaling. Moreover, PUFAs can alter the epigenome via modulation of DNA methylation. In this review, we summarize recent investigations linking PUFAs and DNA methylation-associated CRC risk.
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Affiliation(s)
- Mostafa Moradi Sarabi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Reza Mohammadrezaei Khorramabadi
- Department of Biochemistry and Genetics, School of Medicine, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Zohre Zare
- Department of Pharmaceutics, School of Pharmacy, Lorestan University of Medical Sciences, Khorramabad 381251698, Iran
| | - Ebrahim Eftekhar
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas 7919915519, Iran
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27
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Lima J, Teixeira Y, Pimenta C, Felipe AV, Silva TD, Junior EEDL, Saad SS, Deak E, Murray H, Manoukian Forones N. Fecal Genetic Mutations and Human DNA in Colorectal Cancer and Polyps Patients. Asian Pac J Cancer Prev 2019; 20:2929-2934. [PMID: 31653137 PMCID: PMC6982689 DOI: 10.31557/apjcp.2019.20.10.2929] [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: 02/12/2019] [Indexed: 02/06/2023] Open
Abstract
Background: Colorectal cancer (CRC) is one of the most frequent cancers. Genetic mutations in CRC already described can be detected in feces. Microarray methods in feces can represent a new diagnostic tool for CRC and significant improvement at public health. Aim: to analyze stool DNA by human DNA quantify and microarray methods as alternatives to CRC screening. Method: Three methods were analyzed in stool samples: Human DNA Quantify, RanplexCRC and KRAS/BRAF/PIK3CA (KBP) Arrays. Results: KBP array mutations were presented in 60.7% of CRC patients and RanplexCRC Array mutations in 61.1% of CRC patients. Sensitivity and specificity for human DNA quantification was 66% and 82% respectively. Fecal KBP Array had 35% sensitivity and 96% specificity and RanplexCRC Array method had 78% sensitivity and 100% specificity. Conclusion: Microarray methods showed promise as potential biomarkers for CRC screening; however, these methods had to be optimized to improve accuracy and applicability by clinical routine.
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Affiliation(s)
- Jacqueline Lima
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Yolanda Teixeira
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Célia Pimenta
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Aledson Vitor Felipe
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Tiago Donizetti Silva
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | | | - Sarhan Sydney Saad
- Surgery Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Elisabeth Deak
- Surgery Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
| | - Helena Murray
- Randox Laboratories Ltd., Crumlin, Co. Antrim, United Kingdom
| | - Nora Manoukian Forones
- Oncology Group, Gastroenterology Division, Medicine Department, Universidade Federal de Sao Paulo, São Paulo, Brazil
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28
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Park YS, Kim DS, Cho SW, Park JW, Jeon SJ, Moon TJ, Kim SH, Son BK, Oh TJ, An S, Kim JH, Chae JD. Analysis of Syndecan-2 Methylation in Bowel Lavage Fluid for the Detection of Colorectal Neoplasm. Gut Liver 2019; 12:508-515. [PMID: 29730903 PMCID: PMC6143447 DOI: 10.5009/gnl17357] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 01/05/2018] [Accepted: 02/03/2018] [Indexed: 02/06/2023] Open
Abstract
Background/Aims Syndecan-2 (SDC2) methylation was previously reported as a sensitive serologic biomarker for the early detection of colorectal cancer (CRC). The purpose of this study was to investigate whether SDC2 methylation is detectable in precancerous lesions and to determine the feasibility of using SDC2 methylation for the detection of CRC and precancerous lesions in bowel lavage fluid (BLF). Methods A total of 190 BLF samples were collected from the rectum at the beginning of colonoscopy from patients with colorectal neoplasm and healthy normal individuals. Fourteen polypectomy specimens were obtained during colonoscopy. A bisulfite pyrosequencing assay and quantitative methylation-specific polymerase chain reaction were conducted to measure SDC2 methylation in tissues and BLF DNA. Results SDC2 methylation was positive in 100% of villous adenoma (VA) and high-grade dysplasia, and hyperplastic polyp samples; 88.9% of tubular adenoma samples; and 0% of normal mucosa samples. In the BLF DNA test forSDC2 methylation, the sensitivity for detecting CRC and VA was 80.0% and 64.7%, respectively, at a specificity of 88.9%. The BLF of patients with multiple tubular adenomas, single tubular adenoma and hyperplastic polyps showed 62.8%, 26.7% and 28.6% rates of methylation-positive SDC2, respectively. Conclusions Our results demonstrated that SDC2 methylation was a frequent event in precancerous lesions and showed high potential in BLF for detecting patients with colorectal neoplasm.
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Affiliation(s)
- Young Sook Park
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Dong Shin Kim
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Sang Woo Cho
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Jong Won Park
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Sang Jin Jeon
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Tae Ju Moon
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Seong Hwan Kim
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Byoung Kwan Son
- Division of Gastroenterology, Department of Internal Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | | | | | - Jeong Hwan Kim
- Department of Family Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
| | - Jeong Don Chae
- Department of Laboratory Medicine, Eulji General Hospital, Eulji University School of Medicine, Seoul, Korea
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29
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Liu R, Su X, Long Y, Zhou D, Zhang X, Ye Z, Ma J, Tang T, Wang F, He C. A systematic review and quantitative assessment of methylation biomarkers in fecal DNA and colorectal cancer and its precursor, colorectal adenoma. MUTATION RESEARCH-REVIEWS IN MUTATION RESEARCH 2019; 779:45-57. [PMID: 31097151 DOI: 10.1016/j.mrrev.2019.01.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 11/15/2018] [Accepted: 01/16/2019] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) arises from accumulated genetic and epigenetic alterations, which provide the possibility to identify tumor-specific biomarkers by analyzing fecal DNA. Methylation status in human genes from tumor tissue is highlighted as promising biomarker in the early detection of CRC. A number of studies have documented altered methylation levels in DNA extracted from stool samples, but generated heterogeneous results. We performed a systematic review and quantitative assessment of existing studies to compare levels of DNA methylation in most frequently studied genes and their diagnostic value in CRC and its precursor, colorectal adenoma, with their counterparts in healthy subjects. Robust searches of the literature were performed in our study with explicit strategies and definite inclusion/exclusion criteria. Pooled data revealed that methylation levels of SFRP2, SFRP1, TFPI2, BMP3, NDRG4, SPG20, and BMP3 plus NDRG4 genes exceeded a sensitivity of 70% and a specificity of 80% for CRC detection. The DOR of the seven candidate biomarkers ranged from 19.80 to 334.33, indicating a good diagnostic power in discriminating cancer from normal tissues. The AUC range was from 0.88 to 0.95, indicating a good or very good discriminatory performance. When test results for BMP3 and NDRG4 were combined, the DOR of CRC detection was 98.36, which was higher than that for BMP3 and NDRG4 separately. As for adenoma detection, the DOR of methylated NDRG4 is higher than that for CRC (CRC vs. adenoma: 54.86 vs. 57.22). Both the sensitivity and specificity of NDRG4 for adenoma detection exceeded 70%. These findings demonstrate the eligibility and feasibility of DNA methylation as a minimally invasive biomarker in feces in the diagnosis of CRC and adenoma. The use of DNA from human stools has the potential to be readily applicable to detect aberrant DNA methylation levels among many subjects for CRC early screening.
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Affiliation(s)
- Rongbin Liu
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Ultrasound, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China; Guangdong Provincial Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xuan Su
- Department of Head and Neck, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, China
| | - Yakang Long
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dalei Zhou
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xiao Zhang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zulu Ye
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jiangjun Ma
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Tao Tang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fang Wang
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
| | - Caiyun He
- Department of Molecular Diagnostics, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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30
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Abstract
Cell-free DNA can be evaluated for the epigenetic component. Epigenetic alterations consist of changes in gene functions that do not involve changes in DNA sequence. The mainly studied epigenetic alteration is DNA methylation occurring at CpG islands in the promoter regions for which several literature data showed clinical relevance. This chapter is an overview of the epigenetic alterations detected in cell-free DNA.
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31
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Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6:869-881. [PMID: 30568941 PMCID: PMC6288499 DOI: 10.12998/wjcc.v6.i15.869] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Maria Borzì
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
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32
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Mojtabanezhad Shariatpanahi A, Yassi M, Nouraie M, Sahebkar A, Varshoee Tabrizi F, Kerachian MA. The importance of stool DNA methylation in colorectal cancer diagnosis: A meta-analysis. PLoS One 2018; 13:e0200735. [PMID: 30024936 PMCID: PMC6053185 DOI: 10.1371/journal.pone.0200735] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2017] [Accepted: 07/02/2018] [Indexed: 12/18/2022] Open
Abstract
A large number of tumor-related methylated genes have been suggested to be of diagnostic and prognostic values for CRC when analyzed in patients' stool samples; however, reported sensitivities and specificities have been inconsistent and widely varied. This meta-analysis was conducted to assess the detection accuracy of stool DNA methylation assay in CRC, early stages of CRC (advanced adenoma, non-advanced adenomas) and hyperplastic polyps, separately. We searched MEDLINE, Web of Science, Scopus and Google Scholar databases until May 1, 2016. From 469 publications obtained in the initial literature search, 38 studies were included in the final analysis involving 4867 individuals. The true positive, false positive, true negative and false negative of a stool-based DNA methylation biomarker using all single-gene tests considering a certain gene; regardless of a specific gene were pooled and studied in different categories. The sensitivity of different genes in detecting different stages of CRC ranged from 0% to 100% and the specificities ranged from 73% to 100%. Our results elucidated that SFRP1 and SFRP2 methylation possessed promising accuracy for detection of not only CRC (DOR: 31.67; 95%CI, 12.31-81.49 and DOR: 35.36; 95%CI, 18.71-66.84, respectively) but also the early stages of cancer, adenoma (DOR: 19.72; 95%CI, 6.68-58.25 and DOR: 13.20; 95%CI, 6.01-28.00, respectively). Besides, NDRG4 could be also considered as a significant diagnostic marker gene in CRC (DOR: 24.37; 95%CI, 10.11-58.73) and VIM in adenoma (DOR: 15.21; 95%CI, 2.72-85.10). In conclusion, stool DNA hypermethylation assay based on the candidate genes SFRP1, SFRP2, NDRG4 and VIM could offer potential diagnostic value for CRC based on the findings of this meta-analysis.
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Affiliation(s)
| | - Maryam Yassi
- Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran
| | - Mehdi Nouraie
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States of America
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Mohammad Amin Kerachian
- Cancer Genetics Research Unit, Reza Radiotherapy and Oncology Center, Mashhad, Iran
- Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Medical Genetics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- * E-mail: ,
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33
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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Labianca R, Merelli B. Screening and Diagnosis for Colorectal Cancer: Present and Future. TUMORI JOURNAL 2018. [DOI: 10.1177/548.6506] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
| | - Barbara Merelli
- Unit of Medical Oncology, Ospedali Riuniti di Bergamo, Italy
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35
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Saroja B, SelwinMich Priyadharson A. Adaptive pillar K-means clustering-based colon cancer detection from biopsy samples with outliers. COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING: IMAGING & VISUALIZATION 2017. [DOI: 10.1080/21681163.2017.1350603] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- B. Saroja
- School of Electrical and Computing, Vel Tech University, Avadi, Chennai
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36
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Soares F, Becker K, Anzanello MJ. A hierarchical classifier based on human blood plasma fluorescence for non-invasive colorectal cancer screening. Artif Intell Med 2017; 82:1-10. [PMID: 28939302 DOI: 10.1016/j.artmed.2017.09.004] [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] [Received: 06/07/2017] [Revised: 08/15/2017] [Accepted: 09/12/2017] [Indexed: 01/06/2023]
Abstract
Colorectal cancer (CRC) a leading cause of death by cancer, and screening programs for its early identification are at the heart of the increasing survival rates. To motivate population participation, non-invasive, accurate, scalable and cost-effective diagnosis methods are required. Blood fluorescence spectroscopy provides rich information that can be used for cancer identification. The main challenges in analyzing blood fluorescence data for CRC classification are related to its high dimensionality and inherent variability, especially when analyzing a small number of samples. In this paper, we present a hierarchical classification method based on plasma fluorescence to identify not only CRC, but also adenomas and other non-malignant colorectal findings that may require further medical investigation. A feature selection algorithm is proposed to deal with the high dimensionality and select discriminant fluorescence wavelengths. These are used to train a binary support vector machine (SVM) in the first level to identify the CRC samples. The remaining samples are then presented to a one-class SVM trained on healthy subjects to detect deviant samples, and thus non-malignant findings. This hierarchical design, together with the one class-SVM, aims to reduce the effects of small samples and high variability. Using a dataset analyzed in previous studies comprised of 12,341 wavelengths, we achieved much superior results. Sensitivity and specificity are 0.87 and 0.95 for CRC detection, and 0.60 and 0.79 for non-malignant findings, respectively. Compared to related work, the proposed method presented a better accuracy, required fewer features, and provides a unified approach that expands CRC detection to non-malignant findings.
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Affiliation(s)
- Felipe Soares
- Institute of Informatics - Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Porto Alegre, RS, Brazil.
| | - Karin Becker
- Institute of Informatics - Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves, 9500, Porto Alegre, RS, Brazil.
| | - Michel J Anzanello
- Department of Industrial Engineering - Universidade Federal do Rio Grande do Sul, Av. Osvaldo Aranha, 99-5° andar, Porto Alegre, RS, Brazil.
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37
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Lugli N, Sotiriou SK, Halazonetis TD. The role of SMARCAL1 in replication fork stability and telomere maintenance. DNA Repair (Amst) 2017. [PMID: 28623093 DOI: 10.1016/j.dnarep.2017.06.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
SMARCAL1 (SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A-Like 1), also known as HARP, is an ATP-dependent annealing helicase that stabilizes replication forks during DNA damage. Mutations in this gene are the cause of Schimke immune-osseous dysplasia (SIOD), an autosomal recessive disorder characterized by T-cell immunodeficiency and growth dysfunctions. In this review, we summarize the main roles of SMARCAL1 in DNA repair, telomere maintenance and replication fork stability in response to DNA replication stress.
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Affiliation(s)
- Natalia Lugli
- Department of Molecular Biology, University of Geneva, Switzerland
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38
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Wang R, Du L, Yang X, Jiang X, Duan W, Yan S, Xie Y, Zhu Y, Wang Q, Wang L, Yang Y, Wang C. Identification of long noncoding RNAs as potential novel diagnosis and prognosis biomarkers in colorectal cancer. J Cancer Res Clin Oncol 2016; 142:2291-301. [PMID: 27591862 DOI: 10.1007/s00432-016-2238-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 08/30/2016] [Indexed: 12/15/2022]
Abstract
BACKGROUND Colorectal cancer (CRC) is prevalent worldwide, and improvements in timely and effective diagnosis are imperatively needed. We aimed to identify potential long noncoding RNA (lncRNA) biomarkers for CRC diagnosis along with prognosis prediction. METHODS LncRNA expression profiles were studied by microarray in paired tumor and normal tissues from six patients with CRC. The expression levels of candidate lncRNAs were analyzed in 80 pairs of tissues and two independent cohorts of serum samples. Receiver-operating characteristic (ROC) curves were employed to evaluate the performance of the lncRNAs identified. The correlation between lncRNAs and disease-specific survival rate of CRC patients was assessed to explore prognostic potential. RESULTS Four lncRNAs (BANCR, NR_026817, NR_029373, and NR_034119) were identified to be significantly dysregulated in both tissue and serum samples with consistent pattern, and a panel was established based on this result. The performance of the 4-lncRNA panel was measured with an area under the ROC curve (AUC) of 0.881. The corresponding AUCs of the panel for patients with TNM stageI, II and III were 0.774, 0.844 and 0.949, respectively, significantly higher than that of CEA. Kaplan-Meier analysis showed that patients with low levels of NR_029373 and NR_034119 had significantly lower disease-specific survival rate (p = 0.013 and 0.044, respectively). Multivariate Cox analysis demonstrated that NR_029373 and NR_034119 were both independently associated with disease-specific survival rate (p = 0.013 and 0.038, respectively). CONCLUSIONS Our study established a distinctive 4-lncRNA panel with considerable diagnostic value and identified NR_029373 and NR_034119 as potential biomarkers for CRC prognosis prediction.
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Affiliation(s)
- Rui Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Lutao Du
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Xiaoyun Yang
- Department of Gastroenterology, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Xiumei Jiang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Weili Duan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Suzhen Yan
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Yujiao Xie
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Yuntao Zhu
- Department of Clinical Laboratory, Jinxiang County People's Hospital, Jining, 272000, Shandong Province, China
| | - Qingliang Wang
- Department of Medical Affairs Management, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Lili Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Yongmei Yang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, 107 Wenhua Xi Road, Jinan, 250012, Shandong Province, China.
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39
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Babaei H, Mohammadi M, Salehi R. DNA methylation analysis of secreted frizzled-related protein 2 gene for the early detection of colorectal cancer in fecal DNA. Niger Med J 2016; 57:242-5. [PMID: 27630389 PMCID: PMC4995817 DOI: 10.4103/0300-1652.188357] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background: The early detection of colorectal cancer (CRC) with high sensitivity screening is essential for the reduction of cancer-specific mortality. Abnormally methylated genes that are responsible for the pathogenesis of cancers can be used as biomarkers for the detection of CRC. The methylation status of the secreted frizzled-related protein 2 (SFRP2) gene was evaluated for their use as a marker in the noninvasive detection of CRC. Materials and Methods: Methylation-specific polymerase chain reaction was performed to analyze the promoter CpG methylation of SFRP2 in the fecal DNA of 25 patients with CRC and 25 individuals exhibiting normal colonoscopy results. Results: Promoter methylation levels of SFRP2 in CRC patients and in healthy controls were 60% and 8%, respectively. Methylation of the SFRP2 promoter in fecal DNA is associated with the presence of colorectal tumors. Conclusion: Hence, the detection of aberrantly methylated DNA in fecal samples may present a promising, noninvasive screening method for CRC.
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Affiliation(s)
- Hadi Babaei
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mohsen Mohammadi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Rasoul Salehi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
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40
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Rasmussen SL, Krarup HB, Sunesen KG, Pedersen IS, Madsen PH, Thorlacius-Ussing O. Hypermethylated DNA as a biomarker for colorectal cancer: a systematic review. Colorectal Dis 2016; 18:549-61. [PMID: 26998585 DOI: 10.1111/codi.13336] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Accepted: 02/03/2016] [Indexed: 12/11/2022]
Abstract
AIM Improved methods for early detection of colorectal cancer (CRC) are essential for increasing survival. Hypermethylated DNA in blood or stool has been proposed as a biomarker for CRC. Biochemical methods have improved in recent years, and several hypermethylated genes that are sensitive and specific for CRC have been proposed. Articles describing the use of hypermethylated promoter regions in blood or stool as biomarkers for CRC were systematically reviewed. METHOD A systematic literature search was performed using the Medline, Web of Science and Embase databases. Studies were included if they analysed hypermethylated genes from stool or blood samples in correlation with CRC. Studies in languages other than English and those based on animal models or cell lines were excluded. RESULTS The literature search yielded 74 articles, including 43 addressing blood samples and 31 addressing stool samples. In blood samples, hypermethylated ALX4, FBN2, HLTF, P16, TMEFF1 and VIM were associated with poor prognosis, hypermethylated APC, NEUROG1, RASSF1A, RASSF2A, SDC2, SEPT9, TAC1 and THBD were detected in early stage CRC and hypermethylated P16 and TFPI2 were associated with CRC recurrence. In stool samples, hypermethylated BMP3, PHACTR3, SFRP2, SPG20, TFPI2 and TMEFF2 were associated with early stage CRC. CONCLUSION Hypermethylation of the promoters of specific genes measured in blood or stool samples could be used as a CRC biomarker and provide prognostic information. The majority of studies, however, include only a few patients with poorly defined control groups. Further studies are therefore needed before hypermethylated DNA can be widely applied as a clinical biomarker for CRC detection and prognosis.
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Affiliation(s)
- S L Rasmussen
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - H B Krarup
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - K G Sunesen
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - I S Pedersen
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - P H Madsen
- Section of Molecular Diagnostics, Clinical Biochemistry and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark
| | - O Thorlacius-Ussing
- Department of Gastrointestinal Surgery and Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
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41
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Fu BC, Randolph TW, Lim U, Monroe KR, Cheng I, Wilkens LR, Le Marchand L, Hullar MAJ, Lampe JW. Characterization of the gut microbiome in epidemiologic studies: the multiethnic cohort experience. Ann Epidemiol 2016; 26:373-9. [PMID: 27039047 PMCID: PMC4892953 DOI: 10.1016/j.annepidem.2016.02.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/03/2016] [Accepted: 02/26/2016] [Indexed: 12/30/2022]
Abstract
PURPOSE The development of next-generation sequencing and accompanying bioinformatics tools has revolutionized characterization of microbial communities. As interest grows in the role of the human microbiome in health and disease, so does the need for well-powered, robustly designed epidemiologic studies. Here, we discuss sources of bias that can arise in gut microbiome research. METHODS Research comparing methods of specimen collection, preservation, processing, and analysis of gut microbiome samples is reviewed. Although selected studies are primarily based on the gut, many of the same principles are applicable to samples derived from other anatomical sites. Methods for participant recruitment and sampling of the gut microbiome implemented in an ongoing population-based study, the Multiethnic Cohort (MEC), are also described. RESULTS Variation in methodologies can influence the results of human microbiome studies. To help minimize bias, techniques such as sample homogenization, addition of internal standards, and quality filtering should be adopted in protocols. Within the MEC, participant response rates to stool sample collection were comparable to other studies, and in-home stool sample collection yields sufficient high-quality DNA for gut microbiome analysis. CONCLUSIONS Application of standardized and quality controlled methods in human microbiome studies is necessary to ensure data quality and comparability among studies.
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Affiliation(s)
- Benjamin C Fu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, University of Washington, Seattle
| | - Timothy W Randolph
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Unhee Lim
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu
| | - Kristine R Monroe
- Department of Preventive Medicine, University of Southern California, Los Angeles
| | - Iona Cheng
- Cancer Prevention Institute of California, Fremont; Stanford Cancer Institute, Stanford, CA
| | - Lynne R Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu
| | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, University of Hawaii at Manoa, Honolulu
| | - Meredith A J Hullar
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Johanna W Lampe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Epidemiology, University of Washington, Seattle.
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Hashimoto Y, Zumwalt TJ, Goel A. DNA methylation patterns as noninvasive biomarkers and targets of epigenetic therapies in colorectal cancer. Epigenomics 2016; 8:685-703. [PMID: 27102979 DOI: 10.2217/epi-2015-0013] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aberrant DNA methylation is frequently detected in gastrointestinal tumors, and can therefore potentially be used to screen, diagnose, prognosticate, and predict colorectal cancers (CRCs). Although colonoscopic screening remains the gold standard for CRC screening, this procedure is invasive, expensive, and suffers from poor patient compliance. Methylated DNA is an attractive choice for a biomarker substrate because CRCs harbor hundreds of aberrantly methylated genes. Furthermore, abundance in extracellular environments and resistance to degradation and enrichment in serum, stool, and other noninvasive bodily fluids, allows quantitative measurements of methylated DNA biomarkers. This article describes the most important studies that investigated the efficacy of serum- or stool-derived methylated DNA as population-based screening biomarkers in CRC, details several mechanisms and factors that control DNA methylation, describes a better use of prevailing technologies that discover novel DNA methylation biomarkers, and illustrates the diversity of demethylating agents and their applicability toward clinical impact.
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Affiliation(s)
- Yutaka Hashimoto
- Center for Translational Genomics & Oncology, Baylor Scott & White Research Institute & Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Timothy J Zumwalt
- Center for Translational Genomics & Oncology, Baylor Scott & White Research Institute & Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
| | - Ajay Goel
- Center for Translational Genomics & Oncology, Baylor Scott & White Research Institute & Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
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Zhai RL, Xu F, Zhang P, Zhang WL, Wang H, Wang JL, Cai KL, Long YP, Lu XM, Tao KX, Wang GB. The Diagnostic Performance of Stool DNA Testing for Colorectal Cancer: A Systematic Review and Meta-Analysis. Medicine (Baltimore) 2016; 95:e2129. [PMID: 26844449 PMCID: PMC4748866 DOI: 10.1097/md.0000000000002129] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Revised: 10/21/2015] [Accepted: 11/01/2015] [Indexed: 12/13/2022] Open
Abstract
This meta-analysis was designed to evaluate the diagnostic performance of stool DNA testing for colorectal cancer (CRC) and compare the performance between single-gene and multiple-gene tests.MEDLINE, Cochrane, EMBASE databases were searched using keywords colorectal cancers, stool/fecal, sensitivity, specificity, DNA, and screening. Sensitivity analysis, quality assessments, and performance bias were performed for the included studies.Fifty-three studies were included in the analysis with a total sample size of 7524 patients. The studies were heterogeneous with regard to the genes being analyzed for fecal genetic biomarkers of CRC, as well as the laboratory methods being used for each assay. The sensitivity of the different assays ranged from 2% to 100% and the specificity ranged from 81% to 100%. The meta-analysis found that the pooled sensitivities for single- and multigene assays were 48.0% and 77.8%, respectively, while the pooled specificities were 97.0% and 92.7%. Receiver operator curves and diagnostic odds ratios showed no significant difference between both tests with regard to sensitivity or specificity.This meta-analysis revealed that using assays that evaluated multiple genes compared with single-gene assays did not increase the sensitivity or specificity of stool DNA testing in detecting CRC.
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Affiliation(s)
- Rong-Lin Zhai
- From the Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China
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Kristiansen S, Sölétormos G. Clinical Utility of Solid Tumor Epigenetics. MEDICAL EPIGENETICS 2016:459-471. [DOI: 10.1016/b978-0-12-803239-8.00025-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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45
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Dhont L, Mascaux C, Belayew A. The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor? Cell Mol Life Sci 2016; 73:129-47. [PMID: 26472339 PMCID: PMC11108516 DOI: 10.1007/s00018-015-2060-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2015] [Revised: 09/21/2015] [Accepted: 10/01/2015] [Indexed: 12/21/2022]
Abstract
The Helicase-like Transcription Factor (HLTF) belongs to the SWI/SNF family of proteins involved in chromatin remodeling. In addition to its role in gene transcription, HLTF has been implicated in DNA repair, which suggests that this protein acts as a tumor suppressor. Accumulating evidence indicates that HLTF expression is altered in various cancers via two mechanisms: gene silencing through promoter hypermethylation or alternative mRNA splicing, which leads to the expression of truncated proteins that lack DNA repair domains. In either case, the alteration of HLTF expression in cancer has a poor prognosis. In this review, we gathered published clinical and molecular data on HLTF. Our purposes are (a) to address whether HLTF alterations could be considered as cancer drivers or passengers and (b) to determine whether its different functions (transcription or DNA repair) could be diverted in clonal selection during cancer progression.
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Affiliation(s)
- Ludovic Dhont
- Laboratory of Molecular Biology, University of Mons, Avenue du Champ de Mars 6, Pentagone 3A, B-7000 Mons, Belgium
- Laboratory of Medicine and Pathobiology, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, 14th floor, Toronto, ON M5G 1L7 Canada
| | - Céline Mascaux
- Laboratory of Medicine and Pathobiology, University of Toronto, Toronto Medical Discovery Tower, 101 College Street, 14th floor, Toronto, ON M5G 1L7 Canada
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Toronto, ON M5G 2L9 Canada
| | - Alexandra Belayew
- Laboratory of Molecular Biology, University of Mons, Avenue du Champ de Mars 6, Pentagone 3A, B-7000 Mons, Belgium
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46
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Gerecke C, Scholtka B, Löwenstein Y, Fait I, Gottschalk U, Rogoll D, Melcher R, Kleuser B. Hypermethylation of ITGA4, TFPI2 and VIMENTIN promoters is increased in inflamed colon tissue: putative risk markers for colitis-associated cancer. J Cancer Res Clin Oncol 2015; 141:2097-107. [PMID: 25902909 DOI: 10.1007/s00432-015-1972-8] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Accepted: 04/13/2015] [Indexed: 12/18/2022]
Abstract
PURPOSE Epigenetic silencing of tumor suppressor genes is involved in early transforming events and has a high impact on colorectal carcinogenesis. Likewise, colon cancers that derive from chronically inflamed bowel diseases frequently exhibit epigenetic changes. But there is little data about epigenetic aberrations causing colorectal cancer in chronically inflamed tissue. The aim of the present study was to evaluate the aberrant gain of methylation in the gene promoters of VIM, TFPI2 and ITGA4 as putative early markers in the development from inflamed tissue via precancerous lesions toward colorectal cancer. METHODS Initial screening of different cancer cell lines by using methylation-specific PCR revealed a putative colon cancer-specific methylation pattern. Additionally, a demethylation assay was performed to investigate the methylation-dependent gene silencing of ITGA4. The candidate markers were analyzed in colonic tissue specimens from patients with colorectal cancer (n = 15), adenomas (n = 76), serrated lesions (n = 13), chronic inflammation (n = 10) and normal mucosal samples (n = 9). RESULTS A high methylation frequency of VIM (55.6 %) was observed in normal colon tissue, whereas ITGA4 and TFPI2 were completely unmethylated in controls. A significant gain of methylation frequency with progression of disease as well as an age-dependent effect was detectable for TFPI2. ITGA4 methylation frequency was high in precancerous and cancerous tissues as well as in inflammatory bowel diseases (IBD). CONCLUSION The already established methylation marker VIM does not permit a specific and sensitive discrimination of healthy and neoplastic tissue. The methylation markers ITGA4 and TFPI2 seem to be suitable risk markers for inflammation-associated colon cancer.
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Affiliation(s)
- Christian Gerecke
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Bettina Scholtka
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Yvonne Löwenstein
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Isabel Fait
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
| | - Uwe Gottschalk
- Department of Internal Medicine, Gastroenterology and Interventional Endoscopy, Vivantes-Klinikum im Friedrichshain, Berlin, Germany
| | - Dorothee Rogoll
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Ralph Melcher
- Division of Gastroenterology, Department of Medicine II, University of Würzburg, Würzburg, Germany
| | - Burkhard Kleuser
- Department of Nutritional Toxicology, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany.
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Xue M, Lai SC, Xu ZP, Wang LJ. Noninvasive DNA methylation biomarkers in colorectal cancer: A systematic review. J Dig Dis 2015; 16:699-712. [PMID: 26565661 DOI: 10.1111/1751-2980.12299] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Revised: 10/25/2015] [Accepted: 11/08/2015] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To summarize the current evidence on the biomarkers associated with DNA methylation in the screening and diagnosis of colorectal cancer (CRC). METHODS A literature search was conducted on the databases of PubMed and Web of Science to identify articles published from 1 January 2000 to 6 June 2015 with language striction. Stuides focusing on the association between noninvasive biomarkers indicating DNA methylation and CRC were included. RESULTS Altogether 74 studies were finally included in the study. Varied genetic markers in the feces and blood samples were hypermethylated in patients with CRC than in the healthy controls. Some of them could even be detected at the early stage of the tumors. The sensitivity of the genetic markers was superior to that of fecal occult blood test and carcinoembryonic antigen. Multitarget DNA assays using a combination of different methylated genes could improve the diagnostic sensitivity. CONCLUSIONS Genetic markers might be minimally invasive, economical and accurate for the screening and surveillance of CRC. Large multicenter studies evaluating these biomarkers systematically and prospectively not only in CRC but also in other types of cancers are needed in the future.
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Affiliation(s)
- Meng Xue
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
| | - San Chuan Lai
- Institute of Gastroenterology, Zhejiang University.,Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China
| | - Zhi Peng Xu
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University
| | - Liang Jing Wang
- Department of Gastroenterology, The Second Affiliated Hospital, School of Medicine, Zhejiang University.,Institute of Gastroenterology, Zhejiang University
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Xue M, Wang LJ. Value of DNA methylation markers in colorectal cancer screening. Shijie Huaren Xiaohua Zazhi 2015; 23:4626-4635. [DOI: 10.11569/wcjd.v23.i29.4626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Recognizing CRC at an early stage by population-based screening is crucial in the prevention and treatment of CRC. Numerous candidate genes, which play important roles in the development and progression of CRC, have been found to be hyper-methylated in the promoter regions in recent studies. The promoter fragments of those hyper-methylated genes in tumor tissues have also been detected in the blood and fecal specimens, with higher sensitivity and specificity than traditional markers in the screening of CRC, including carcino-embryonic antigen (CEA) and fecal occult blood test. Here, we will discuss what we have already known about the DNA methylation markers for CRC screening and the potential research direction in the future.
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Okugawa Y, Grady WM, Goel A. Epigenetic Alterations in Colorectal Cancer: Emerging Biomarkers. Gastroenterology 2015; 149:1204-1225.e12. [PMID: 26216839 PMCID: PMC4589488 DOI: 10.1053/j.gastro.2015.07.011] [Citation(s) in RCA: 556] [Impact Index Per Article: 55.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2015] [Revised: 07/13/2015] [Accepted: 07/20/2015] [Indexed: 02/06/2023]
Abstract
Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. One of the fundamental processes driving the initiation and progression of CRC is the accumulation of a variety of genetic and epigenetic changes in colonic epithelial cells. Over the past decade, major advances have been made in our understanding of cancer epigenetics, particularly regarding aberrant DNA methylation, microRNA (miRNA) and noncoding RNA deregulation, and alterations in histone modification states. Assessment of the colon cancer "epigenome" has revealed that virtually all CRCs have aberrantly methylated genes and altered miRNA expression. The average CRC methylome has hundreds to thousands of abnormally methylated genes and dozens of altered miRNAs. As with gene mutations in the cancer genome, a subset of these epigenetic alterations, called driver events, are presumed to have a functional role in CRC. In addition, the advances in our understanding of epigenetic alterations in CRC have led to these alterations being developed as clinical biomarkers for diagnostic, prognostic, and therapeutic applications. Progress in this field suggests that these epigenetic alterations will be commonly used in the near future to direct the prevention and treatment of CRC.
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Affiliation(s)
- Yoshinaga Okugawa
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington.
| | - Ajay Goel
- Gastrointestinal Cancer Research Laboratory, Division of Gastroenterology, Department of Internal Medicine, Charles A. Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
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