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Saadh MJ, Allela OQB, Kareem RA, Baldaniya L, Ballal S, Vashishth R, Parmar M, Sameer HN, Hamad AK, Athab ZH, Adil M. Prognostic gene expression profile of colorectal cancer. Gene 2025; 955:149433. [PMID: 40122415 DOI: 10.1016/j.gene.2025.149433] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Revised: 02/26/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Colorectal cancer is a major global health burden, with significant heterogeneity in clinical outcomes among patients. Identifying robust prognostic gene expression signatures can help stratify patients, guide treatment decisions, and improve clinical management. This review provides an overview of current prognostic gene expression profiles in colorectal cancer research. We have synthesized evidence from numerous published studies investigating the association between tumor gene expression patterns and patient survival outcomes. The reviewed literature reveals several promising gene signatures that have demonstrated the ability to predict disease-free survival and overall survival in CRC patients, independent of standard clinicopathological risk factors. These genes are crucial in fundamental biological processes, including cell cycle control, epithelial-mesenchymal transition, and immune regulation. The implementation of prognostic gene expression tests in clinical practice holds great potential for enabling more personalized management strategies for colorectal cancer.
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Affiliation(s)
- Mohamed J Saadh
- Faculty of Pharmacy, Middle East University, Amman 11831, Jordan.
| | | | | | - Lalji Baldaniya
- Marwadi University Research Center, Department of Pharmacy, Faculty of Health Sciences, Marwadi University, Rajkot 360003 Gujarat, India.
| | - Suhas Ballal
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to be University), Bangalore, Karnataka, India.
| | - Raghav Vashishth
- Department of Surgery, National Institute of Medical Sciences, NIMS University Rajasthan, Jaipur, India.
| | - Manisha Parmar
- Chandigarh Pharmacy College, Chandigarh Group of Colleges-Jhanjeri, Mohali, Punjab, India.
| | - Hayder Naji Sameer
- Collage of Pharmacy, National University of Science and Technology, Dhi Qar 64001, Iraq.
| | | | - Zainab H Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq.
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Huang J, Chen M, Chan VCW, Liu X, Zhong C, Lin J, Hang J, Zhong CC, Yuan J, Wong MCS. The Cost-Effectiveness of a Multi-Target Stool DNA-Based Screening (COLOTECT), FIT, Colonoscopy and No Screening for Colorectal Cancer. Cancer Rep (Hoboken) 2025; 8:e70176. [PMID: 40275466 PMCID: PMC12021674 DOI: 10.1002/cnr2.70176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 02/16/2025] [Accepted: 02/20/2025] [Indexed: 04/26/2025] Open
Abstract
BACKGROUND Around 1.9 million new cases and 1 million deaths worldwide were attributed to colorectal cancer (CRC) in 2020. AIMS The aims of this study are to assess the cost-effectiveness of a multi-target stool DNA-based screening strategy, COLOTECT, compared to faecal immunochemical tests (FIT), colonoscopy, and no screening in the Asian population to inform more choices for policymakers in colorectal cancer screening. METHOD AND RESULTS We assume that 100,000 persons aged 50 undergo annual FIT, annual COLOTECT multi-target testing, or colonoscopies every 10 years until age 75. The data used in this study was retrieved from different sources including the Hong Kong Cancer Registry and previously published studies on the population aged 50 to 75 years old between 2010 and 2023. This study accessed the most cost-effective screening strategy available. If a positive result of FIT or COLOTECT were observed, the participants would undergo a colonoscopy. The participants who used the colonoscopy as the main screening method conducted colonoscopies every 3 years. The Markov models were utilized to compare the outcomes from different strategies including life-years saved, years of life lost, and incremental cost-effectiveness ratio (primary outcome). The highest ICER was observed in colonoscopy (USD 160808), followed by FIT (USD 108952), and COLOTECT (USD 82206). A higher detection rate of CRC (COLOTECT: 39.3% vs. FIT: 4.5%), more CRC cases prevented (1272 vs. 146), and life-years saved (2295 vs. 337) were observed in the COLOTECT strategy than in FIT. Additionally, a lower total cost per life-year saved of COLOTECT (USD 180097) was observed than colonoscopy (USD 238356), which identified the more affordable and cost-saving COLOTECT strategy. CONCLUSION This study highlighted the better performance of COLOTECT than FIT in detecting CRC. Additionally, given its lower cost and higher acceptance, the COLOTECT strategy might be more cost-effective than colonoscopy for massive CRC screening.
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Affiliation(s)
- Junjie Huang
- Jockey Club School of Public Health and Primary Care, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
- Centre for Health Education and Health Promotion, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
| | - Mingtao Chen
- Jockey Club School of Public Health and Primary Care, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
| | - Victor C. W. Chan
- Jockey Club School of Public Health and Primary Care, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
| | - Xianjing Liu
- Department of Radiology and Nuclear MedicineErasmus MC University Medical CenterRotterdamthe Netherlands
| | - Chaoying Zhong
- Department of Electrical Engineering and AutomationGuangdong Ocean UniversityZhanjiangGuangdongChina
| | - Jianli Lin
- Peking‐Tsinghua Center for Life SciencesAcademy for Advanced Interdisciplinary Studies, Peking UniversityBeijingChina
| | - Junjie Hang
- Cancer Hospital & Shenzhen HospitalBeijingChinese Academy of Medical Sciences and Peking Union Medical CollegeChina
| | - Claire Chenwen Zhong
- Jockey Club School of Public Health and Primary Care, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
- Centre for Health Education and Health Promotion, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
| | - Jinqiu Yuan
- Clinical Research Center, Big Data CenterThe Seventh Afliated Hospital, Sun Yat‐Sen UniversityGuangzhouGuangdongChina
| | - Martin C. S. Wong
- Jockey Club School of Public Health and Primary Care, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
- Centre for Health Education and Health Promotion, Faculty of MedicineThe Chinese University of Hong KongHong Kong SAR
- The School of Public HealthPeking UniversityBeijingChina
- The School of Public HealthThe Chinese Academy of Medical Sciences and The Peking Union Medical CollegesBeijingChina
- The School of Public HealthFudan UniversityShanghaiChina
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Blatkiewicz M, Białas P, Taryma-Leśniak O, Mazgaj S, Hukowska-Szematowicz B, Jankowska A. Exploring vimentin expression and its protein interactors across diverse cancer types via the cancer genome atlas datasets: a comprehensive analysis. Rep Pract Oncol Radiother 2025; 30:88-99. [PMID: 40242413 PMCID: PMC11999022 DOI: 10.5603/rpor.104142] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 12/19/2024] [Indexed: 04/18/2025] Open
Abstract
Background The global burden of cancer is escalating, with millions of individuals diagnosed and succumbing to the disease each year. Early detection is crucial for improving patient outcomes, yet many cancers are identified at advanced stages. Vimentin (VIM) has emerged as a promising biomarker with significant diagnostic and prognostic potential. Materials and methods This study investigates VIM expression and promoter methylation across various cancers using The Cancer Genome Atlas (TCGA) datasets. Additionally, we analyze protein-protein interactions and mutation frequencies using advanced bioinformatics tools. Results Our findings reveal that VIM is overexpressed in seven cancer types, including cholangiocarcinoma, glioblastoma multiforme, and breast invasive carcinoma. Notably, VIM expression is correlated with promoter methylation in specific cancers. Furthermore, we identify complex protein interactions involving VIM, highlighting its role in critical cellular processes such as proliferation and apoptosis. Conclusion These insights emphasize Vimentin's multifaceted role in cancer, suggesting its potential as both a therapeutic target and a diagnostic marker.
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Affiliation(s)
- Małgorzata Blatkiewicz
- Department of Histology and Embryology, Poznan University of Medical Sciences, Poznań, Poland
| | - Piotr Białas
- Chair and Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
| | - Olga Taryma-Leśniak
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Szczecin, Poland
| | - Szymon Mazgaj
- Institute of Biology, University of Szczecin, Szczecin, Poland
- Department of Blood Preparation, Regional Center for Blood Donation and Blood Treatment in Zielona Góra, Zielona Góra, Poland
| | - Beata Hukowska-Szematowicz
- Institute of Biology, University of Szczecin, Szczecin, Poland
- Molecular Biology and Biotechnology Center, University of Szczecin, Szczecin, Poland
| | - Anna Jankowska
- Chair and Department of Cell Biology, Poznan University of Medical Sciences, Poznań, Poland
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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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Kim CW, Kim H, Kim HR, Won DD, Nam WJ, Min BS, Oh TJ, An S, Lee SH. A Stool DNA-Based SDC2 Methylation Test for the Early Detection of Colorectal Cancer in an Asymptomatic, High-Risk Population: A Multicenter Prospective Randomized Trial. Am J Gastroenterol 2025; 120:614-622. [PMID: 39292188 DOI: 10.14309/ajg.0000000000003044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 07/22/2024] [Indexed: 09/19/2024]
Abstract
INTRODUCTION Noninvasive stool DNA-based methylation testing has emerged as an effective strategy for the early colorectal cancer (CRC) detection. Syndecan-2 ( SDC2 ) methylation frequently occurs in all stages of CRC; therefore, the aim of this study was to evaluate the clinical performance of a stool DNA-based SDC2 methylation test for detecting CRC in asymptomatic or high-risk CRC populations. METHODS This multicenter prospective study was conducted to determine the clinical performance of the SDC2 methylation test on stool DNA using real-time polymerase chain reaction. Stool samples were collected from asymptomatic individuals before colonoscopy, and the test results were independently analyzed through comparison with colonoscopic findings and pathological outcomes as reference standards. RESULTS Of the 1,124 evaluable participants, 20 had CRC, 73 had advanced adenomatous polyps (≥1.0 cm), 469 had nonadvanced adenomatous polyps (<1.0 cm), 178 had non-neoplastic polyps, and 384 had negative colonoscopy results. The stool SDC2 methylation test had a sensitivity and specificity of 95.0% and 81.5%, respectively, for detecting CRC, while the sensitivity for detecting advanced adenomatous polyps and CRC was 58.1%. The rate of adenoma detection increased with polyp size ( P < 0.01), and sensitivity was not associated with CRC stage ( P = 0.864). DISCUSSION The stool DNA-based SDC2 methylation test attained a high sensitivity for CRC detection in an asymptomatic high-risk population. Further large-scale clinical studies are required to validate the clinical utility of this test as a population-based CRC screening tool.
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Affiliation(s)
- Chang Woo Kim
- Department of Surgery, Ajou University Hospital, Ajou University School of Medicine, Suwon, South Korea
| | - Hyunjin Kim
- Department of Surgery, Koo Hospital, Daegu, South Korea
| | - Hyoung Rae Kim
- Department of Surgery, Busan Hangun Hospital, Busan, South Korea
| | - Daeyeon David Won
- Department of Surgery, Seoul Songdo Colorectal Hospital, Seoul, South Korea
| | - Woo Jung Nam
- Department of Surgery, Seoul Songdo Colorectal Hospital, Seoul, South Korea
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | - Byung Soh Min
- Department of Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
| | | | | | - Suk-Hwan Lee
- Department of Surgery, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, South Korea
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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: 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: 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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Dang T, Guan X, Cui L, Ruan Y, Chen Z, Zou H, Lan Y, Liu C, Zhang Y. Epigenetics and immunotherapy in colorectal cancer: progress and promise. Clin Epigenetics 2024; 16:123. [PMID: 39252116 PMCID: PMC11385519 DOI: 10.1186/s13148-024-01740-9] [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: 11/13/2023] [Accepted: 09/02/2024] [Indexed: 09/11/2024] Open
Abstract
Colorectal cancer (CRC) is a common malignant tumor with the third and second highest incidence and mortality rates among various malignant tumors. Despite significant advancements in the present therapy for CRC, the majority of CRC cases feature proficient mismatch repair/microsatellite stability and have no response to immunotherapy. Therefore, the search for new treatment options holds immense importance in the diagnosis and treatment of CRC. In recent years, clinical research on immunotherapy combined with epigenetic therapy has gradually increased, which may bring hope for these patients. This review explores the role of epigenetic regulation in exerting antitumor effects through its action on immune cell function and highlights the potential of certain epigenetic genes that can be used as markers of immunotherapy to predict therapeutic efficacy. We also discuss the application of epigenetic drug sensitization immunotherapy to develop new treatment options combining epigenetic therapy and immunotherapy.
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Affiliation(s)
- Tianjiao Dang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Xin Guan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Luying Cui
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Yuli Ruan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Zhuo Chen
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Haoyi Zou
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China
| | - Ya Lan
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Chao Liu
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China.
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China.
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China.
| | - Yanqiao Zhang
- Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150001, Heilongjiang, People's Republic of China.
- Key Laboratory of Tumor Immunology in Heilongjiang, Harbin, China.
- Clinical Research Center for Colorectal Cancer in Heilongjiang, Harbin, China.
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Oh CK, Cho YS. Pathogenesis and biomarkers of colorectal cancer by epigenetic alteration. Intest Res 2024; 22:131-151. [PMID: 38295766 PMCID: PMC11079515 DOI: 10.5217/ir.2023.00115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/16/2023] [Accepted: 12/29/2023] [Indexed: 05/12/2024] Open
Abstract
Colorectal cancer (CRC) ranks third in cancer incidence and stands as the second leading cause of cancer-related deaths globally. CRC tumorigenesis results from a cumulative set of genetic and epigenetic alterations, disrupting cancer-regulatory processes like cell proliferation, metabolism, angiogenesis, cell death, invasion, and metastasis. Key epigenetic modifications observed in cancers encompass abnormal DNA methylation, atypical histone modifications, and irregularities in noncoding RNAs, such as microRNAs and long noncoding RNAs. The advancement in genomic technologies has positioned these genetic and epigenetic shifts as potential clinical biomarkers for CRC patients. This review concisely covers the fundamental principles of CRC-associated epigenetic changes, and examines in detail their emerging role as biomarkers for early detection, prognosis, and treatment response prediction.
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Affiliation(s)
- Chang Kyo Oh
- Division of Gastroenterology, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Young-Seok Cho
- Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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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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Rezkitha YAA, Panenggak NSR, Lusida MI, Rianda RV, Mahmudah I, Pradana AD, Uchida T, Miftahussurur M. Detecting colorectal cancer using genetic and epigenetic biomarkers: screening and diagnosis. J Med Life 2024; 17:4-14. [PMID: 38737656 PMCID: PMC11080499 DOI: 10.25122/jml-2023-0269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 11/01/2023] [Indexed: 05/14/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent types of cancer, with high incidence rates and mortality globally. The extended timeframe for developing CRC allows for the potential screening and early identification of the disease. Furthermore, studies have shown that survival rates for patients with cancer are increased when diagnoses are made at earlier stages. Recent research suggests that the development of CRC, including its precancerous lesion, is influenced not only by genetic factors but also by epigenetic variables. Studies suggest epigenetics plays a significant role in cancer development, particularly CRC. While this approach is still in its early stages and faces challenges due to the variability of CRC, it shows promise as a potential method for understanding and addressing the disease. This review examined the current evidence supporting genetic and epigenetic biomarkers for screening and diagnosis. In addition, we also discussed the feasibility of translating these methodologies into clinical settings. Several markers show promising potential, including the methylation of vimentin (VIM), syndecan-2 (SDC2), and septin 9 (SEPT9). However, their application as screening and diagnostic tools, particularly for early-stage CRC, has not been fully optimized, and their effectiveness needs validation in large, multi-center patient populations. Extensive trials and further investigation are required to translate genetic and epigenetic biomarkers into practical clinical use. biomarkers, diagnostic biomarkers.
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Affiliation(s)
- Yudith Annisa Ayu Rezkitha
- Doctoral Program of Medical Science, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Nur Syahadati Retno Panenggak
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
| | - Maria Inge Lusida
- Institute of Tropical Disease, Indonesia-Japan Collaborative Research Center for Emerging and Re-Emerging Infectious Diseases, Universitas Airlangga, Surabaya, Indonesia
| | - Raissa Virgy Rianda
- Department of Child Health, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Isna Mahmudah
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
| | - Aditya Doni Pradana
- Department of Emergency Services, Kendal Islamic Hospital, Kendal, Indonesia
- Department of Cardiology and Vascular Medicine, Faculty of Medicine, Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia
| | - Tomohisa Uchida
- Department of Molecular Pathology, Faculty of Medicine, Oita University, Yufu, Japan
| | - Muhammad Miftahussurur
- Helicobacter pylori and Microbiota Study Group, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia
- Division of Gastroentero-Hepatology, Department of Internal Medicine, Faculty of Medicine-Dr Soetomo Teaching Hospital, Universitas Airlangga, Surabaya, Indonesia
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11
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Órdenes P, Carril Pardo C, Elizondo-Vega R, Oyarce K. Current Research on Molecular Biomarkers for Colorectal Cancer in Stool Samples. BIOLOGY 2023; 13:15. [PMID: 38248446 PMCID: PMC10813333 DOI: 10.3390/biology13010015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 12/08/2023] [Accepted: 12/10/2023] [Indexed: 01/23/2024]
Abstract
Colorectal cancer (CRC) is one of the most diagnosed cancers worldwide, with a high incidence and mortality rate when diagnosed late. Currently, the methods used in healthcare to diagnose CRC are the fecal occult blood test, flexible sigmoidoscopy, and colonoscopy. However, the lack of sensitivity and specificity and low population adherence are driving the need to implement other technologies that can identify biomarkers that not only help with early CRC detection but allow for the selection of more personalized treatment options. In this regard, the implementation of omics technologies, which can screen large pools of biological molecules, coupled with molecular validation, stands out as a promising tool for the discovery of new biomarkers from biopsied tissues or body fluids. This review delves into the current state of the art in the identification of novel CRC biomarkers that can distinguish cancerous tissue, specifically from fecal samples, as this could be the least invasive approach.
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Affiliation(s)
- Patricio Órdenes
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
| | - Claudio Carril Pardo
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
| | - Roberto Elizondo-Vega
- Laboratorio de Biología Celular, Facultad de Ciencias Biológicas, Universidad de Concepción, Concepción 4070386, Chile;
| | - Karina Oyarce
- Laboratorio de Neuroinmunología, Facultad de Medicina y Ciencia, Universidad San Sebastián, Sede Concepción, Concepción 4030000, Chile; (P.Ó.); (C.C.P.)
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12
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Lukacova E, Burjanivova T, Podlesniy P, Grendar M, Turyova E, Kasubova I, Laca L, Mikolajcik P, Kudelova E, Vanochova A, Miklusica J, Mersakova S, Lasabova Z. Hypermethylated GRIA4, a potential biomarker for an early non-invasive detection of metastasis of clinically known colorectal cancer. Front Oncol 2023; 13:1205791. [PMID: 37476382 PMCID: PMC10354553 DOI: 10.3389/fonc.2023.1205791] [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: 04/14/2023] [Accepted: 06/12/2023] [Indexed: 07/22/2023] Open
Abstract
Introduction Colorectal cancer (CRC) can develop through several dysregulated molecular pathways, including the serrated pathway, characterized by CpG island methylator (CIMP) phenotype. Although the tumor tissue is a commonly tested material, sample types such as stool or plasma, bring a new, non-invasive approach. Several cancer-related methylated genes have been identified in CRC patients, including gene GRIA4, showing promising diagnostic potential. The aim of our study was to develop a sensitive droplet digital PCR (ddPCR) assay to examine GRIA4 hypermethylation status in CRC patients and evaluate its diagnostic potential in tissue and liquid biopsy samples. Methods In total, 23 patients participated in this study, 7 patients with primary CRC and 16 patients with liver metastasis of clinically known CRC. We obtained tumor and non-tumor tissues (N=17), blood samples pre- and post-surgery (N=22), and blood of five volunteers without a personal cancer history. We have developed and optimized a ddPCR assay for GRIA4 hypermethylation detection, from tissue and plasma samples. Results We detected significantly increased GRIA4 methylation in tumor tissues compared to their adjacent non-tumor tissue, p<0.0001. Receiver operating characteristic (ROC) analysis defined cutoff values to separate primary tumors and metastases from non-tumor colon/rectum, specifically 36.85% for primary tumors and 34.81% for metastases. All primary tumors were above this threshold. When comparing the methylation levels of metastatic vs. non-tumor tissue, a smaller increase was observed in liver metastasis versus colon tissue (3.6× gain; p=0.001), then in liver metastasis versus adjacent liver tissue (17.4× gain; p<0.0001). On average, GRIA4 hypermethylation in primary tumor plasma was 2.8-fold higher (p=0.39), and in metastatic plasma, 16.4-fold higher (p=0.0011) compared to healthy individuals. Hypermethylation in metastatic plasma was on average 5.9 times higher (p=0.051) than in primary tumor plasma. After tumor removal surgery, average hypermethylation decrease in plasma was 1.6× for primary (p=0.037) and 4.5× for metastatic patients (p=0.023). Discussion Based on our data, it can be inferred that GRIA4 serves as a tissue specific biomarker for the colon/rectum tissue, thus is suitable for cancer classification. This biomarker showed the potential to be an attractive target for early non-invasive detection of metastases of clinically known CRC, although additional analysis has to be performed.
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Affiliation(s)
- Eva Lukacova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - Tatiana Burjanivova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - Petar Podlesniy
- Centro Investigacion Biomedica en Red Enfermedades Neurodegenerativas (CiberNed), Madrid, Spain
| | - Marian Grendar
- Laboratory of Bioinformatics and Biostatistics, Biomedical Center Martin JFM CU, Commenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - Eva Turyova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - Ivana Kasubova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Ludovit Laca
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Peter Mikolajcik
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Eva Kudelova
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Andrea Vanochova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
| | - Juraj Miklusica
- Clinic of Surgery and Transplant Center, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Sandra Mersakova
- Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia
| | - Zora Lasabova
- Department of Molecular Biology and Genomics, Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin (JFM CU), Martin, Slovakia
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13
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Zhang Y, Wang Y, Zhang B, Li P, Zhao Y. Methods and biomarkers for early detection, prediction, and diagnosis of colorectal cancer. Biomed Pharmacother 2023; 163:114786. [PMID: 37119736 DOI: 10.1016/j.biopha.2023.114786] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 04/17/2023] [Accepted: 04/24/2023] [Indexed: 05/01/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common digestive diseases worldwide. It has steadily ascended to the top three cancers in terms of incidence and mortality. The primary cause is the inability to diagnose it at an early stage. Therefore, early detection and diagnosis are essential for colorectal cancer prevention. Although there are now various methods for CRC early detection, in addition to recent developments in surgical and multimodal therapy, the poor prognosis and late detection of CRC still remain significant. Thus, it is important to investigate novel technologies and biomarkers to improve the sensitization and specification of CRC diagnosis. Here, we present some common methods and biomarkers for early detection and diagnosis of CRC, we hope this review will encourage the adoption of screening programs and the clinical use of these potential molecules as biomarkers for CRC early detection and prognosis.
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Affiliation(s)
- Yue Zhang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China
| | - Yin Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China; Key Laboratory of Birth Regulation and Control Technology of National Health Commission of China, Maternal and Child Health Care Hospital of Shandong Province affiliated to Qingdao University, Shandong Province, China
| | - Bingqiang Zhang
- Key Laboratory of Cancer and Immune Cells of Qingdao, Qingdao 266021, China
| | - Peifeng Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
| | - Yi Zhao
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao 266021, China.
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14
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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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15
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Jayasinghe M, Prathiraja O, Caldera D, Jena R, Coffie-Pierre JA, Silva MS, Siddiqui OS. Colon Cancer Screening Methods: 2023 Update. Cureus 2023; 15:e37509. [PMID: 37193451 PMCID: PMC10182334 DOI: 10.7759/cureus.37509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/12/2023] [Indexed: 05/18/2023] Open
Abstract
Colorectal cancer (CRC) is a significant cause of morbidity and mortality worldwide. National screening guidelines have been implemented to identify and remove precancerous polyps before they become cancer. Routine CRC screening is advised for people with average risk starting at age 45 because it is a common and preventable malignancy. Various screening modalities are currently in use, ranging from stool-based tests (fecal occult blood test (FOBT), fecal immunochemical test (FIT), and FIT-DNA test), radiologic tests (computed tomographic colonography (CTC), double contrast barium enema), and visual endoscopic examinations (flexible sigmoidoscopy (FS), colonoscopy, and colon capsule endoscopy (CCE)) with their varying sensitivity and specificity. Biomarkers also play a vital role in assessing the recurrence of CRC. This review offers a summary of the current screening options, including biomarkers available to detect CRC, highlighting the benefits and challenges encompassing each screening modality.
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Affiliation(s)
| | | | | | - Rahul Jena
- Neurology/Internal Medicine, Bharati Vidyapeeth Medical College/Bharati Hospital, Pune, IND
| | | | | | - Ozair S Siddiqui
- Medicine, GMERS Medical College and Hospital, Dharpur-Patan, Patan, IND
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16
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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: 7] [Impact Index Per Article: 3.5] [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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17
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Baghel VS, Shinde S, Sinha V, Dixit V, Tiwari AK, Saxena S, Vishvakarma NK, Shukla D, Bhatt P. Inhibitors targeting epigenetic modifications in cancer. TRANSCRIPTION AND TRANSLATION IN HEALTH AND DISEASE 2023:287-324. [DOI: 10.1016/b978-0-323-99521-4.00007-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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18
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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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19
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Khan ES, Danckwardt S. Pathophysiological Role and Diagnostic Potential of R-Loops in Cancer and Beyond. Genes (Basel) 2022; 13:genes13122181. [PMID: 36553448 PMCID: PMC9777984 DOI: 10.3390/genes13122181] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/07/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022] Open
Abstract
R-loops are DNA-RNA hybrids that play multifunctional roles in gene regulation, including replication, transcription, transcription-replication collision, epigenetics, and preserving the integrity of the genome. The aberrant formation and accumulation of unscheduled R-loops can disrupt gene expression and damage DNA, thereby causing genome instability. Recent links between unscheduled R-loop accumulation and the abundance of proteins that modulate R-loop biogenesis have been associated with numerous human diseases, including various cancers. Although R-loops are not necessarily causative for all disease entities described to date, they can perpetuate and even exacerbate the initially disease-eliciting pathophysiology, making them structures of interest for molecular diagnostics. In this review, we discuss the (patho) physiological role of R-loops in health and disease, their surprising diagnostic potential, and state-of-the-art techniques for their detection.
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Affiliation(s)
- Essak S. Khan
- Posttranscriptional Gene Regulation, Cancer Research and Experimental Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
- German Consortium for Translational Cancer Research (DKTK), DKFZ Frankfurt-Mainz, 60590 Frankfurt am Main, Germany
| | - Sven Danckwardt
- Posttranscriptional Gene Regulation, Cancer Research and Experimental Hemostasis, University Medical Center Mainz, 55131 Mainz, Germany
- Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
- Center for Thrombosis and Hemostasis (CTH), University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Rhine-Main, 55131 Mainz, Germany
- Correspondence:
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20
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Wele P, Wu X, Shi H. Sex-Dependent Differences in Colorectal Cancer: With a Focus on Obesity. Cells 2022; 11:cells11223688. [PMID: 36429114 PMCID: PMC9688265 DOI: 10.3390/cells11223688] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/07/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and has the second highest cancer-related mortality in the world. The incident rates of CRC vary country-wise; however, population studies and data from different countries show a general increase in the CRC rate in young adults, males, and females ≥65 years. CRC incidence is affected by age, sex, environmental, dietary, hormonal, and lifestyle factors. Obesity is a known disease that is spreading rapidly throughout the world. A large body of literature indicates that, among many conditions, obesity is the increasing cause of CRC. Even though obesity is one of the known factors for CRC development, limited studies are available that explain the mechanistic link between obesity, sex hormones, and CRC development. Thus, this review summarizes the literature and aims to understand sex-dependent differences in CRC, especially in the context of obesity.
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Affiliation(s)
- Prachi Wele
- Department of Biology, Miami University, Oxford, OH 45056, USA
| | - Xian Wu
- Department of Kinesiology, Nutrition, and Health, Miami University, Oxford, OH 45056, USA
| | - Haifei Shi
- Department of Biology, Miami University, Oxford, OH 45056, USA
- Correspondence: ; Tel.: +1-513-529-3162
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21
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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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22
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Ma L, Qin G, Gai F, Jiang Y, Huang Z, Yang H, Yao S, Du S, Cao Y. A novel method for early detection of colorectal cancer based on detection of methylation of two fragments of syndecan-2 (SDC2) in stool DNA. BMC Gastroenterol 2022; 22:191. [PMID: 35436855 PMCID: PMC9014784 DOI: 10.1186/s12876-022-02264-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 04/04/2022] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Methylated SDC2 has been proved as a diagnostic marker for human colorectal cancer (CRC), noninvasive stool DNA-based methylation testing also emerges as a novel approach for detecting CRC. The aim of this study was to evaluate the clinical performance of stool DNA-based SDC2 methylation test by a new qPCR detection reagent for early detection of CRC. METHODS A new qPCR detection reagent contained two differentially methylated regions in SDC2 CpG islands for the detection of CRC was used in this study. Performance of the SDC2 methylation detection reagent was evaluated by analyzing limit of detection, precision, and specificity. The effect of interfering substances on assay performance was also tested. 339 subjects (102 CRC patients, 50 patients with advanced adenomas, 39 patients with non-advanced adenomas, 18 colitis patients and 130 normal individuals) from the China-Japan Friendship Hospital were evaluated. Approximately 2.5 g of stool sample was collected from each participant. Stool DNA was extracted and bisulfite-converted, followed by qPCR assay, which contained two pairs of primers for the methylation detection of two fragments of the SDC2 gene (named SDC2-A and SDC2-B). The diagnostic value of this test in CRC was evaluated by calculating receiver operating characteristic (ROC) curve, and value of the area under the curve (AUC). RESULTS The test kit was able to detect methylated SDC2 in stool DNA samples with concentrations as low as 90 copies/μL in 100% of replicates. The sensitivity for detecting CRC by methylated SDC2-A alone was 85.29% (95% CI 77.03-91.00%) with a specificity of 96.15% (95% CI 91.08-98.58%). The sensitivity by methylated SDC2-B alone was 83.33% (95% CI 74.82-89.42%) with a specificity of 97.69% (95% CI 93.14-99.51%). However, when methylated SDC2-A and methylated SDC2-B were combined, the sensitivity for CRC detection improved to 87.25% (95% CI 79.27-92.53%) with a specificity of 94.62% (95% CI 89.11-97.56%). Further, the detection reagent achieved ROC-AUC 0.874 (95% CI 0.822-0.927) for SDC2-A, 0.906 (95% CI 0.859-0.952) for SDC2-B, and 0.939 (95% CI 0.902-0.977) for SDC2-Combine A&B. CONCLUSIONS This study validated the capability of stool DNA-based SDC2 methylation test for early screening of CRC, and combined detection of two fragments of SDC2 gene could improve detection sensitivity.
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Affiliation(s)
- Liang Ma
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Geng Qin
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Fei Gai
- Medical Business Unit, Amoy Diagnostics Co. Ltd., Xiamen, 361026, China
| | - Yongwei Jiang
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Zhan Huang
- Medical Business Unit, Amoy Diagnostics Co. Ltd., Xiamen, 361026, China
| | - Hui Yang
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Shukun Yao
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, 100029, China
| | - Shiyu Du
- Department of Gastroenterology, China-Japan Friendship Hospital, Beijing, 100029, China.
| | - Yongtong Cao
- Clinical Laboratory, China-Japan Friendship Hospital, Beijing, 100029, China.
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Yue C, Zhang Y, Wang Y, Zhang Z, Zhang M, Wang H, Chen W, Shang Z, Xin Y, Zhang X, Zhang Y. The Application Value of Syndecan-2 Gene Methylation for Colorectal Cancer Diagnosis: A Clinical Study and Meta-Analyses. Front Med (Lausanne) 2022; 9:753545. [PMID: 35372441 PMCID: PMC8964598 DOI: 10.3389/fmed.2022.753545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 02/07/2022] [Indexed: 12/02/2022] Open
Abstract
Objective Syndecan-2 (SDC2) methylation has been previously reported as a sensitive biomarker for the early detection of colorectal cancer (CRC). Droplet digital PCR (ddPCR) is the latest development of PCR technology. It can accurately detect and quantify the target sequence of nucleic acid. ddPCR is widely used in research and clinical diagnosis. In the present study, we aimed to develop a ddPCR method to detect SDC2 gene methylation and evaluate the diagnostic value of SDC2 gene methylation. Methods First, a ddPCR method was developed to measure SDC2 methylation in stool samples collected from 51 cases of normal, 23 cases of adenoma, and 86 cases of CRC. Subsequently, a meta-analysis of existing studies was conducted to judge the diagnostic value of SDC2 gene methylation in CRC. PUBMED, EMBASE, Web of Science, and Scopus databases were searched for relative studies. Meta-analysis was performed using Meta Disc 1.4 and STATA 15.0 software. Results The ddPCR showed that the linearity, sensitivity, and specificity for the detection of SDC2 gene methylation could be down to 0.1% methylation level and 5 ng of methylated DNA input. In 109 cases of CRC, 107 cases could be detected, and the sensitivity was 98.17%. The median value of the percentage of methylated reference (PMR) in colorectal adenoma and CRC patients was significantly higher compared with the normal individuals (p < 0.001). In addition, we found that the PMR value was associated with the clinical staging of CRC. The difference of PMR in stage II and stage IIIA was statistically significant (p < 0.05). Moreover, the meta-analysis showed that 11 out of 87 studies were identified to report the feasibility of SDC2 gene methylation as a method to diagnose early CRC. The pooled sensitivity and specificity of SDC2 gene methylation test for CRC were 0.80 [95% CI (0.68–0.88)] and 0.93 [95% CI (0.91–0.94)], respectively. The pooled diagnostic odds ratio (DOR) and area under curve (AUC) were 52.46 [95% CI (30.43–90.45)] and 0.94 [95% CI (0.92, 0.96)], respectively. Conclusions The ddPCR method was more sensitive and convenient to detect SDC2 gene methylation, and the pooled analysis showed that methylated SDC2 was a valuable biomarker for the non-invasive detection of CRC.
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Affiliation(s)
- Congbo Yue
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yaping Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yanlei Wang
- Department of General Surgery, Qilu Hospital of Shandong University, Jinan, China
| | | | - Mengjiao Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Huayang Wang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Wendan Chen
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Ziqi Shang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yiwei Xin
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Xin Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
| | - Yi Zhang
- Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, China
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24
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Müller D, Győrffy B. DNA methylation-based diagnostic, prognostic, and predictive biomarkers in colorectal cancer. Biochim Biophys Acta Rev Cancer 2022; 1877:188722. [PMID: 35307512 DOI: 10.1016/j.bbcan.2022.188722] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 03/13/2022] [Indexed: 12/12/2022]
Abstract
DNA methylation is an epigenetic mechanism regulating gene expression. Changes in DNA methylation were suggested to be useful biomarkers for diagnosis, and for the determination of prognosis and treatment response. Here, we provide an overview of methylation-based biomarkers in colorectal cancer. First, we start with the two methylation-based diagnostic biomarkers already approved for colorectal cancer, SEPT9 and the combination of NDRG4 and BMP3. Then, we provide a list-based overview of new biomarker candidates depending on the sample source including plasma, stool, urine, and surgically removed tumor tissues. The most often identified markers like SDC2, VIM, APC, MGMT, SFRP1, SFRP2, and NDRG4 have distinct functions previously linked to tumor progression. Although numerous studies have identified tumor-specific methylation changes, most of these alterations were observed in a single study only. The lack of validation in independent samples means low reproducibility and is a major limitation. The genome-wide determination of methylation status (methylome) can provide data to solve these issues. In the third section of the review, methylome studies focusing on different aspects related to CRC, including precancerous lesions, CRC-specific changes, molecular subtypes, aging, and chemotherapy response are summarized. Notably, techniques simultaneously analyzing a large set of regions can also uncover epigenetic regulation of genes which have not yet been associated with tumorigenesis previously. A remaining constraint of studies published to date is the low patient number utilized in these preventing the identification of clinically valuable biomarker candidates. Either future large-scale studies or the integration of already available methylome-level data will be necessary to uncover biomarkers sufficiently robust for clinical application.
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Affiliation(s)
- Dalma Müller
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary
| | - Balázs Győrffy
- Dept. of Bioinformatics, Semmelweis University, Budapest, Hungary; Cancer Biomarker Research Group, RCNS, Budapest, Hungary.
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25
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Vimentin: Regulation and pathogenesis. Biochimie 2022; 197:96-112. [DOI: 10.1016/j.biochi.2022.02.003] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 01/11/2022] [Accepted: 02/09/2022] [Indexed: 12/18/2022]
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26
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Toden S, Goel A. Non-coding RNAs as liquid biopsy biomarkers in cancer. Br J Cancer 2022; 126:351-360. [PMID: 35013579 PMCID: PMC8810986 DOI: 10.1038/s41416-021-01672-8] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 11/17/2021] [Accepted: 12/07/2021] [Indexed: 01/12/2023] Open
Abstract
Although non-coding RNAs have long been considered as non-functional "junk" RNAs, accumulating evidence in the past decade indicates that they play a critical role in pathogenesis of various cancers. In addition to their biological significance, the recognition that their expression levels are frequently dysregulated in multiple cancers have fueled the interest for exploiting their clinical potential as cancer biomarkers. In particular, microRNAs (miRNAs), a subclass of small non-coding RNAs that epigenetically modulate gene-transcription, have become one of the most well-studied substrates for the development of liquid biopsy biomarkers for cancer patients. The emergence of high-throughput sequencing technologies has enabled comprehensive molecular characterisation of various non-coding RNA expression profiles in multiple cancers. Furthermore, technological advances for quantifying lowly expressed RNAs in the circulation have facilitated robust identification of previously unrecognised and undetectable biomarkers in cancer patients. Here we summarise the latest progress on the utilisation of non-coding RNAs as non-invasive cancer biomarkers. We evaluated the suitability of multiple non-coding RNA types as blood-based cancer biomarkers and examined the impact of recent technological breakthroughs on the development of non-invasive molecular biomarkers in cancer.
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Affiliation(s)
- Shusuke Toden
- Molecular Stethoscope Inc., South San Francisco, CA 94080 USA
| | - Ajay Goel
- grid.410425.60000 0004 0421 8357Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Monrovia, CA 91016 USA ,grid.410425.60000 0004 0421 8357City of Hope Comprehensive Cancer Center, Duarte, CA 91010 USA
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Kim JC, Bodmer WF. Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer. Ann Coloproctol 2021; 37:368-381. [PMID: 34961301 PMCID: PMC8717071 DOI: 10.3393/ac.2021.00878.0125] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 10/21/2021] [Indexed: 12/20/2022] Open
Abstract
The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.
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Affiliation(s)
- Jin Cheon Kim
- Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea.,Laboratory of Cancer Biology and Genetics, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea
| | - Walter F Bodmer
- Cancer and Immunogenetics Laboratory, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom
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28
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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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Cao LJ, Peng XL, Xue WQ, Zhang R, Zhang JB, Zhou T, Wu ZY, Li GR, Wang TM, He YQ, Yang DW, Liao Y, Tong XT, Wang F, Chen KX, Zhang SH, Zhu LQ, Ding PR, Jia WH. A fecal-based test for the detection of advanced adenoma and colorectal cancer: a case-control and screening cohort study. BMC Med 2021; 19:250. [PMID: 34689777 PMCID: PMC8543798 DOI: 10.1186/s12916-021-02123-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 09/13/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Screening is a confirmed way to reduce the incidence and mortality rates of CRC. This study aimed to identify a fecal-based, noninvasive, and accurate method for detection of colorectal cancer (CRC) and advanced adenoma (AA). METHODS Through detection in tissue (n = 96) and fecal samples (n = 88) and tested in an independent group of fecal samples (n = 294), the methylated DNA marker ITGA4 and bacterial markers Fusobacterium nucleatum (Fn) and Pepetostreptococcusanaerobius (Pa) were identified from the candidate biomarkers for CRC and AA detection. A prediction score (pd-score) was constructed using the selected markers and fecal immunochemical test (FIT) for distinguishing AA and CRC from healthy subjects by logistic regression method. The diagnostic performance of the pd-score was compared with FIT and validated in the external validation cohort (n = 117) and in a large CRC screening cohort. RESULTS The pd-score accurately identified AA and CRC from healthy subjects with an area under the curve (AUC) of 0.958, at a specificity of 91.37%; the pd-score showed sensitivities of 95.38% for CRC and 70.83% for AA, respectively. In the external validation cohort, the sensitivities of the pd-score for CRC and AA detection were 94.03% and 80.00%, respectively. When applied in screening, the pd-score identified 100% (11/11) of CRC and 70.83% (17/24) of AA in participants with both colonoscopy results and qualified fecal samples, showing an improvement by 41.19% compared to FIT. CONCLUSIONS The current study developed a noninvasive and well-validated approach for AA and CRC detection, which could be applied widely as a diagnostic and screening test.
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Affiliation(s)
- Lian-Jing Cao
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Department of Radiation Oncology, Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiao-Lin Peng
- Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, People's Republic of China
| | - Wen-Qiong Xue
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Rong Zhang
- Department of Endoscopy and Laser, Sun Yat-Sen University Cancer Center, Guangzhou, People's Republic of China
| | - Jiang-Bo Zhang
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Ting Zhou
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
- Biobank of Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Zi-Yi Wu
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Gai-Rui Li
- Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, People's Republic of China
| | - Tong-Min Wang
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Yong-Qiao He
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Da-Wei Yang
- School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Ying Liao
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Xia-Ting Tong
- School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China
| | - Fang Wang
- Department of Radiation Oncology, Affiliated Cancer Hospital and Institute of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China
| | - Ke-Xin Chen
- Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, Tianjin Key Laboratory of Breast Cancer Prevention and Therapy, Ministry of Education, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China
| | - Shi-Hong Zhang
- Department of Laboratory Medicine, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China
| | - Li-Qing Zhu
- Shenzhen Nanshan Center for Chronic Disease Control, Shenzhen, People's Republic of China
| | - Pei-Rong Ding
- Department of Colorectal Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
| | - Wei-Hua Jia
- State Key Laboratory of Oncology in South China Guangzhou, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
- Biobank of Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
- School of Public Health, Sun Yat-Sen University, Guangzhou, People's Republic of China.
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30
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Multiple Biomarker-Combined Screening for Colorectal Cancer Based on Bisulfate Conversion-Free Detection of Fecal DNA Methylation. BIOMED RESEARCH INTERNATIONAL 2021; 2021:1479748. [PMID: 34621892 PMCID: PMC8492253 DOI: 10.1155/2021/1479748] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/19/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
To evaluate the applicability of bisulfate conversion-free methylation assay based on enzyme digestion in fecal screening for colorectal cancer (CRC). Stool samples were collected from a total of 1142 participants with intestinal abnormalities, including 180 positive cases, 60 advanced adenomas, and 902 negative cases. DNA from reference cell lines and clinical samples was extracted and digested with an enzyme to detect the methylation of CRC markers SEPT9, SDC2, NDRG4, SFRP2, and BMP3 genes. Statistical analysis was then used to determine the ability of the markers, both individually and in combination, to detect CRC and adenoma. Our results showed that the enzyme digestion method could suitably detect DNA marker methylation in as low as 1% of the cell lines. BMP3 had a considerably low detection rate in all clinical samples, with only 6 positive cases detected out of 180 cancer samples. Our findings showed that the combination of SEPT9, SDC2, and SFRP2 had an area under the receiver operation curve of 0.937, sensitivity of 94.11%, and specificity of 89.21% for detecting CRC. Moreover, the detection sensitivity of adenoma can also reach 38.33%. After innovatively utilizing bisulfate conversion-free methylation assay for CRC screening, this study verified the potential clinical applicability of combining multiple biomarkers for CRC screening in a large number of samples.
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31
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van den Berg I, Smid M, Coebergh van den Braak RRJ, van de Wiel MA, van Deurzen CHM, de Weerd V, Martens JWM, IJzermans JNM, Wilting SM. A panel of DNA methylation markers for the classification of consensus molecular subtypes 2 and 3 in patients with colorectal cancer. Mol Oncol 2021; 15:3348-3362. [PMID: 34510716 PMCID: PMC8637568 DOI: 10.1002/1878-0261.13098] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 08/04/2021] [Accepted: 09/09/2021] [Indexed: 12/25/2022] Open
Abstract
Consensus molecular subtypes (CMSs) can guide precision treatment of colorectal cancer (CRC). We aim to identify methylation markers to distinguish between CMS2 and CMS3 in patients with CRC, for which an easy test is currently lacking. To this aim, fresh‐frozen tumor tissue of 239 patients with stage I‐III CRC was analyzed. Methylation profiles were obtained using the Infinium HumanMethylation450 BeadChip. We performed adaptive group‐regularized logistic ridge regression with post hoc group‐weighted elastic net marker selection to build prediction models for classification of CMS2 and CMS3. The Cancer Genome Atlas (TCGA) data were used for validation. Group regularization of the probes was done based on their location either relative to a CpG island or relative to a gene present in the CMS classifier, resulting in two different prediction models and subsequently different marker panels. For both panels, even when using only five markers, accuracies were > 90% in our cohort and in the TCGA validation set. Our methylation marker panel accurately distinguishes between CMS2 and CMS3. This enables development of a targeted assay to provide a robust and clinically relevant classification tool for CRC patients.
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Affiliation(s)
- Inge van den Berg
- Department of Surgery, Erasmus MC - University Medical Center Rotterdam, The Netherlands
| | - Marcel Smid
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | | | - Mark A van de Wiel
- Department of Epidemiology & Data Science, Amsterdam University Medical Center, Amsterdam Public Health research institute, The Netherlands
| | | | - Vanja de Weerd
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - John W M Martens
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
| | - Jan N M IJzermans
- Department of Surgery, Erasmus MC - University Medical Center Rotterdam, The Netherlands
| | - Saskia M Wilting
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, The Netherlands
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32
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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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Zhang W, Yang C, Wang S, Xiang Z, Dou R, Lin Z, Zheng J, Xiong B. SDC2 and TFPI2 Methylation in Stool Samples as an Integrated Biomarker for Early Detection of Colorectal Cancer. Cancer Manag Res 2021; 13:3601-3617. [PMID: 33958894 PMCID: PMC8096344 DOI: 10.2147/cmar.s300861] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Accepted: 04/07/2021] [Indexed: 12/24/2022] Open
Abstract
Background Detection of aberrant methylated DNA in the stool is an effective early screening method for colorectal cancer (CRC). Previously, reporters identified that syndecan-2 (SDC2) and tissue factor pathway inhibitor 2 (TFPI2) were aberrantly methylated in most CRC tissues. However, the combined diagnostic role of them remains undefined. Our research aimed at probing the role and efficiency of the methylation status of SDC2 and TFPI2 in CRC early screening by using bioinformatics analysis and clinical stool sample validation. Methods The promoter and CpG site methylation levels of SDC2 and TFPI2 and their correlation with clinicopathological characteristics of CRC were analyzed using UALCAN, Methsurv, and Wanderer. UCSC Xena was used to perform survival analyses. LinkedOmics was used to do functional network analysis. DNA was isolated and purified from stool, and quantitative methylation-specific PCR (qMSP) was applied to detect methylatedSDC2 and TFPI2. Results The results showed that promoter and most CpG site methylation levels of SDC2 and TFPI2 were significantly higher in CRC than in normal tissues. Moreover, SDC2 and TFPI2 methylation showed a positive correlation. Functional network analysis suggested that both methylated SDC2 and TFPI2 were involved in tumor cells’ metabolic programs. Besides, there was a higher positive integrated detection rate in CRC (n=61) with a sensitivity of 93.4% and in adenoma (Ade) (n=16) with a sensitivity of 81.3% than normal with a specificity of 94.3% in stool samples. What is more, integration of methylated SDC2 and TFPI2 showed a higher sensitivity and Youden index than a single gene in detecting Adeor CRC. Conclusion Our data indicate that SDC2 and TFPI2 were hypermethylated in CRC, and integrated detection of methylated SDC2 and TFPI2 in stool has the potential to be an effective and noninvasive tool of CRC early screening.
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Affiliation(s)
- Weisong Zhang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Chaogang Yang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Shuyi Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Zhenxian Xiang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Rongzhang Dou
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Zaihuan Lin
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Jinsen Zheng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
| | - Bin Xiong
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Tumor Biological Behaviors & Hubei Cancer Clinical Study Center, Wuhan, 430071, People's Republic of China
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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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35
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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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36
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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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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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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: 148] [Impact Index Per Article: 37.0] [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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C8orf48 inhibits the tumorigenesis of colorectal cancer by regulating the MAPK signaling pathway. Life Sci 2020; 266:118872. [PMID: 33309715 DOI: 10.1016/j.lfs.2020.118872] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/27/2020] [Accepted: 12/01/2020] [Indexed: 11/22/2022]
Abstract
AIMS Colorectal cancer (CRC) is a leading cause of cancer-related death globally. Thus, in this study, we aimed to investigate chromosome 8 open reading frame 48 (C8orf48) as a biomarker for early detection of CRC. MAIN METHODS RNA expression and methylation profiles were downloaded from The Cancer Genome Atlas (TCGA) database. Cell proliferation, migration and invasion assays were performed to confirm the function of C8orf48 in CRC cells. Dual-luciferase reporter assay was used to identify that C8orf48 was the direct target of miR-556. Genomics of Drug Sensitivity in Cancer (GDSC) database, gene set enrichment analysis (GSEA) and western blot analysis were performed to explore the mechanism of C8orf48. KEY FINDINGS we found that C8orf48 is down-regulated in clinical samples of CRC tissues. Enrichment analysis showed that C8orf48 is associated with methylation biomarkers in CRC, and TCGA database confirmed that the methylation of C8orf48 is up-regulated in the early stage of CRC. We further revealed that the overexpression of C8orf48 decreased CRC cell proliferation, migration and invasion. Luciferase reporter indicated that C8orf48 was the direct target of the oncogene miR-556. Additionally, we used GDSC database, GSEA database and western blot analysis to demonstrate that C8orf48 plays a suppressor role in CRC by inhibiting MAPK signaling pathway. SIGNIFICANCE C8orf48 was identified as a biomarker for early detection of CRC for the first time, and might provide novel information for CRC prediction and therapy.
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Bresalier RS, Grady WM, Markowitz SD, Nielsen HJ, Batra SK, Lampe PD. Biomarkers for Early Detection of Colorectal Cancer: The Early Detection Research Network, a Framework for Clinical Translation. Cancer Epidemiol Biomarkers Prev 2020; 29:2431-2440. [PMID: 32299850 PMCID: PMC7572434 DOI: 10.1158/1055-9965.epi-20-0234] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 02/26/2020] [Accepted: 04/09/2020] [Indexed: 12/26/2022] Open
Abstract
Early detection by screening significantly reduces mortality from colorectal cancer, but 40% of guideline-eligible patients are not screened as recommended in the United States. Novel strategies to improve screening uptake overall and efforts to deploy best practices to underserved populations are a high priority for health care. This review focuses on existing biomarkers in practice and those in development with clinical relevance to early detection of colorectal neoplasia, with an emphasis on those developed by investigators of the NCI's Early Detection Research Network. Aberrantly methylated DNA markers (blood and stool), stool-based markers (including fecal immunochemical test-DNA), and a variety of blood-based marker assays in development (protein markers, glycoproteins including mucins, and cell-free DNA tests) are reviewed. Individual markers and biomarker panels, sample resources, and barriers to translating biomarkers to clinical practice are discussed.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."
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Affiliation(s)
- Robert S Bresalier
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - William M Grady
- Clinical Research Division, Fred Hutchinson Cancer Research Center and the Department of Medicine, Division of Gastroenterology, University of Washington School of Medicine, Seattle, Washington
| | - Sanford D Markowitz
- Case Comprehensive Cancer Center and the Division of Hematology-Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Hans Jørgen Nielsen
- Department of Surgical Gastroenterology, Hvidovre Hospital, Hvidovre, Denmark
- The Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Eppley Institute for Research in Cancer and Allied Diseases, Fred and Pamela Buffett Cancer Center, Omaha, Nebraska
| | - Paul D Lampe
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington
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41
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EP4 receptor as a novel promising therapeutic target in colon cancer. Pathol Res Pract 2020; 216:153247. [PMID: 33190014 DOI: 10.1016/j.prp.2020.153247] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 01/17/2023]
Abstract
The most prevalent malignancy that can occur in the gastrointestinal tract is colon cancer. The current treatment options for colon cancer patients include chemotherapy, surgery, radiotherapy, immunotherapy, and targeted therapy. Although the chance of curing the disease in the early stages is high, there is no cure for almost all patients with advanced and metastatic disease. It has been found that over-activation of cyclooxygenase 2 (COX-2), followed by the production of prostaglandin E2 (PGE2) in patients with colon cancer are significantly increased. The tumorigenic function of COX-2 is mainly due to its role in the production of PGE2. PGE2, as a main generated prostanoid, has an essential role in growth and survival of colon cancer cell's. PGE2 exerts various effects in colon cancer cells including enhanced expansion, angiogenesis, survival, invasion, and migration. The signaling of PGE2 via the EP4 receptor has been shown to induce colon tumorigenesis. Moreover, the expression levels of the EP4 receptor significantly affect tumor growth and development. Overexpression of EP4 by various mechanisms increases survival and tumor vasculature in colon cancer cells. It seems that the pathway starting with COX2, continuing with PGE2, and ending with EP4 can promote the spread and growth of colon cancer. Therefore, targeting the COX-2/PGE2/EP4 axis can be considered as a worthy therapeutic approach to treat colon cancer. In this review, we have examined the role and different mechanisms that the EP4 receptor is involved in the development of colon cancer.
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Raut JR, Guan Z, Schrotz-King P, Brenner H. Fecal DNA methylation markers for detecting stages of colorectal cancer and its precursors: a systematic review. Clin Epigenetics 2020; 12:122. [PMID: 32778176 PMCID: PMC7418412 DOI: 10.1186/s13148-020-00904-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023] Open
Abstract
Background DNA methylation biomarkers in stool may have applications in early colorectal cancer (CRC) detection; however, their association with stages of CRC carcinogenesis or their performance in detecting various stages is unclear. We aimed to systematically review the evidence for DNA methylation markers in stool for risk stratification or detection of specific CRC stages, as well as precursors of CRC. Methods We conducted a systematic search in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched PubMed and ISI Web of Knowledge to identify relevant studies published until 14th January 2020. Two reviewers independently extracted data on study population characteristics, candidate genes, methylation measurement methods, odds ratios (ORs), overall and stage-specific sensitivities, specificities, areas under the receiver operating characteristics curve, and p-values for statistical significance for OR and for association of methylation levels with stage. Results Twenty-seven studies that reported stage-specific associations or performances of fecal DNA methylation markers for detecting colorectal neoplasms were identified. All studies used methylation-specific polymerase chain reaction for assessing methylation levels in the promoter or exon 1 regions of targeted genes. However, most studies were underpowered and limited by their case-control design. Furthermore, the stage-specific associations or sensitivities were validated for two markers (hypermethylation of GATA4 and VIM) only. Conclusion Methylation markers in stool may be useful for detection of CRC precursors or CRC staging, but promising candidate markers need to be validated in longitudinal studies on large screening populations, performing epigenome-wide analyses. Identification of stage-specific DNA methylation biomarkers in stool could boost current strategies towards early detection and enable different approaches to precision medicine for CRC.
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Affiliation(s)
- Janhavi R Raut
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.,Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Zhong Guan
- Medical Faculty Heidelberg, University of Heidelberg, Heidelberg, Germany.,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Petra Schrotz-King
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. .,Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. .,German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Niknami Z, Muhammadnejad A, Ebrahimi A, Harsani Z, Shirkoohi R. Significance of E-cadherin and Vimentin as epithelial-mesenchymal transition markers in colorectal carcinoma prognosis. EXCLI JOURNAL 2020; 19:917-926. [PMID: 32665775 PMCID: PMC7355153 DOI: 10.17179/excli2020-1946] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 06/24/2020] [Indexed: 12/23/2022]
Abstract
Colorectal cancer is the most common malignancy of the gastrointestinal tract with very high mortality. One of the most distinguishing features for the establishment of an epithelial-mesenchymal transition phenotype is the alteration of mesenchymal markers and structural adhesion proteins. We investigated the level of Vimentin and E-cadherin expression in relation to invasion and metastasis on colorectal cancer patients. Tissue specimens were collected consecutively from thirty-nine colorectal carcinoma patients during surgeries. The patients were diagnosed and treated between 2013 and 2016. In order to histological staging, tissue sections were prepared from formalin-fixed paraffin-embedded blocks and stained with Hematoxylin and Eosin. Also for evaluating the epithelial-mesenchymal transition markers, E-cadherin and Vimentin, all patient samples were stained and detected via immunohistochemistry, and afterwards the results were analyzed to determine whether these markers could be useful prognostic markers for predicting colorectal cancer patient outcomes. The expression of Vimentin as a mesenchymal marker along with rising grade of cancer, pathological stages, and metastasis to regional lymph nodes increased furthermore, in cancers with vascular invasion, Vimentin value was high. Reversely, the expression of E-cadherin with climbing grade, stages and colon cancer categories decreased and also in cancers with vascular invasion reduced. Variation of the markers had no relation to age and sex. In summary, along with cancer progression level of Vimentin expression varies inversely with E-cadherin expression and by increasing metastasis and invasion the Vimentin expression elevates. Further evaluation in this area might lead to a good method for predicting progressive clone cancer.
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Affiliation(s)
- Zohreh Niknami
- Department of Genetics, Faculty of Science, Islamic Azad University, Damghan, Iran
| | - Ahad Muhammadnejad
- Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Ebrahimi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Zahra Harsani
- Department of Cell and Molecular Biology, Islamic Azad Medical University of Tehran, Tehran, Iran
| | - Reza Shirkoohi
- Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
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Bacolod MD, Mirza AH, Huang J, Giardina SF, Feinberg PB, Soper SA, Barany F. Application of Multiplex Bisulfite PCR-Ligase Detection Reaction-Real-Time Quantitative PCR Assay in Interrogating Bioinformatically Identified, Blood-Based Methylation Markers for Colorectal Cancer. J Mol Diagn 2020; 22:885-900. [PMID: 32407802 DOI: 10.1016/j.jmoldx.2020.03.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 02/14/2020] [Accepted: 03/31/2020] [Indexed: 02/07/2023] Open
Abstract
The analysis of CpG methylation in circulating tumor DNA fragments has emerged as a promising approach for the noninvasive early detection of solid tumors, including colorectal cancer (CRC). The most commonly employed assay involves bisulfite conversion of circulating tumor DNA, followed by targeted PCR, then real-time quantitative PCR (alias methylation-specific PCR). This report demonstrates the ability of a multiplex bisulfite PCR-ligase detection reaction-real-time quantitative PCR assay to detect seven methylated CpG markers (CRC or colon specific), in both simulated (approximately 30 copies of fragmented CRC cell line DNA mixed with approximately 3000 copies of fragmented peripheral blood DNA) and CRC patient-derived cell-free DNAs. This scalable assay is designed for multiplexing and incorporates steps for improved sensitivity and specificity, including the enrichment of methylated CpG fragments, ligase detection reaction, the incorporation of ribose bases in primers, and use of uracil DNA glycosylase. Six of the seven CpG markers (located in promoter regions of PPP1R16B, KCNA3, CLIP4, GDF6, SEPT9, and GSG1L) were identified through integrated analyses of genome-wide methylation data sets for 31 different types of cancer. These markers were mapped to CpG sites at the promoter region of VIM; VIM and SEPT9 are established epigenetic markers of CRC. Additional bioinformatics analyses show that the methylation at these CpG sites negatively correlates with the transcription of their corresponding genes.
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Affiliation(s)
- Manny D Bacolod
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Aashiq H Mirza
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Jianmin Huang
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Sarah F Giardina
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Philip B Feinberg
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York
| | - Steven A Soper
- Department of Mechanical Engineering, The University of Kansas, Lawrence, Kansas
| | - Francis Barany
- Department of Microbiology and Immunology, Weill Cornell Medicine, New York, New York.
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Oh HH, Joo YE. Novel biomarkers for the diagnosis and prognosis of colorectal cancer. Intest Res 2020; 18:168-183. [PMID: 31766836 PMCID: PMC7206347 DOI: 10.5217/ir.2019.00080] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/05/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is among the most common malignancies and remains a major cause of cancer-related death worldwide. Despite recent advances in surgical and multimodal therapies, the overall survival of advanced CRC patients remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. The underlying mechanisms of action resulting in cancer progression are beginning to unravel. The reported molecular and biochemical mechanisms that might contribute to the phenotypic changes in favor of carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, and immune surveillance inhibition. These events may contribute to the development and progression of cancer. A biomarker is a molecule that can be detected in tissue, blood, or stool samples to allow the identification of pathological conditions such as cancer. Thus, it would be beneficial to identify reliable and practical molecular biomarkers that aid in the diagnostic and therapeutic processes of CRC. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. Despite that, the identification of diagnostic, prognostic, and/or predictive biomarkers remains challenging, and previously identified biomarkers might be insufficient to be clinically applicable or offer high patient acceptability. Here, we discuss recent advances in the development of molecular biomarkers for their potential usefulness in early and less-invasive diagnosis, treatment, and follow-up of CRC.
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Affiliation(s)
- Hyung-Hoon Oh
- Department of Internal Medicine, 3rd Fleet Medical Corps, Republic of Korea Navy, Yeongam, Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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Sensi F, D’Angelo E, Piccoli M, Pavan P, Mastrotto F, Caliceti P, Biccari A, Corallo D, Urbani L, Fassan M, Spolverato G, Riello P, Pucciarelli S, Agostini M. Recellularized Colorectal Cancer Patient-derived Scaffolds as in vitro Pre-clinical 3D Model for Drug Screening. Cancers (Basel) 2020; 12:681. [PMID: 32183226 PMCID: PMC7140024 DOI: 10.3390/cancers12030681] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 03/04/2020] [Accepted: 03/12/2020] [Indexed: 12/24/2022] Open
Abstract
Colorectal cancer (CRC) shows highly ineffective therapeutic management. An urgent unmet need is the random assignment to adjuvant chemotherapy of high-risk stage II and stage III CRC patients without any predictive factor of efficacy. In the field of drug discovery, a critical step is the preclinical evaluation of drug cytotoxicity, efficacy, and efficiency. We proposed a patient-derived 3D preclinical model for drug evaluation that could mimic in vitro the patient's disease. Surgically resected CRC tissue and adjacent healthy colon mucosa were decellularized by a detergent-enzymatic treatment. Scaffolds were recellularized with HT29 and HCT116 cells. Qualitative and quantitative characterization of matched recellularized samples were evaluated through histology, immunofluorescences, scanning electron microscopy, and DNA amount quantification. A chemosensitivity test was performed using an increasing concentration of 5-fluorouracil (5FU). In vivo studies were carried out using zebrafish (Danio rerio) animal model. Permeability test and drug absorption were also determined. The decellularization protocol allowed the preservation of the original structure and ultrastructure. Five days after recellularization with HT29 and HCT116 cell lines, the 3D CRC model exhibited reduced sensitivity to 5FU treatments compared with conventional 2D cultures. Calculated the half maximal inhibitory concentration (IC50) for HT29 treated with 5FU resulted in 11.5 µM in 3D and 1.3 µM in 2D, and for HCT116, 9.87 µM in 3D and 1.7 µM in 2D. In xenograft experiments, HT29 extravasation was detected after 4 days post-injection, and we obtained a 5FU IC50 fully comparable to that observed in the 3D CRC model. Using confocal microscopy, we demonstrated that the drug diffused through the repopulated 3D CRC scaffolds and co-localized with the cell nuclei. The bioengineered CRC 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays and provide effective cancer treatment.
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Affiliation(s)
- Francesca Sensi
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Mestre (Venice), Italy;
| | - Edoardo D’Angelo
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
| | - Martina Piccoli
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
| | - Piero Pavan
- Department of Industrial Engineering, University of Padua, 35131 Padua, Italy;
| | - Francesca Mastrotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (F.M.); (P.C.)
| | - Paolo Caliceti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padua, 35131 Padua, Italy; (F.M.); (P.C.)
| | - Andrea Biccari
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
| | - Diana Corallo
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
| | - Luca Urbani
- Institute of Hepatology, Foundation for Liver Research, London SE5 9NT, UK;
- Faculty of Life Sciences & Medicine, King’s College London, London WC2R 2LS, UK
| | - Matteo Fassan
- Surgical Pathology Unit, Department of Medicine, University of Padua, 35100 Padua, Italy;
| | - Gaya Spolverato
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
| | - Pietro Riello
- Department of Molecular Sciences and Nanosystems, Ca’ Foscari University of Venice, 30172 Mestre (Venice), Italy;
| | - Salvatore Pucciarelli
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
| | - Marco Agostini
- Fondazione Istituto di Ricerca Pediatrica Città della Speranza, 35129 Padua, Italy; (F.S.); (M.P.); (D.C.)
- First Surgical Clinic, Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy; (E.D.); (G.S.); (S.P.)
- LIFELAB Program, Consorzio per la Ricerca Sanitaria-CORIS, Veneto Region, 129 Padua, Italy;
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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: 506] [Impact Index Per Article: 101.2] [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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Shahkarami S, Zoghi S, Rezaei N. The Role of DNA Methylation in Cancer. CANCER IMMUNOLOGY 2020:491-511. [DOI: 10.1007/978-3-030-30845-2_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Luo H, Zhao Q, Wei W, Zheng L, Yi S, Li G, Wang W, Sheng H, Pu H, Mo H, Zuo Z, Liu Z, Li C, Xie C, Zeng Z, Li W, Hao X, Liu Y, Cao S, Liu W, Gibson S, Zhang K, Xu G, Xu RH. Circulating tumor DNA methylation profiles enable early diagnosis, prognosis prediction, and screening for colorectal cancer. Sci Transl Med 2020; 12:12/524/eaax7533. [PMID: 31894106 DOI: 10.1126/scitranslmed.aax7533] [Citation(s) in RCA: 272] [Impact Index Per Article: 54.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Accepted: 10/04/2019] [Indexed: 02/05/2023]
Abstract
Circulating tumor DNA (ctDNA) has emerged as a useful diagnostic and prognostic biomarker in many cancers. Here, we conducted a study to investigate the potential use of ctDNA methylation markers for the diagnosis and prognostication of colorectal cancer (CRC) and used a prospective cohort to validate their effectiveness in screening patients at high risk of CRC. We first identified CRC-specific methylation signatures by comparing CRC tissues to normal blood leukocytes. Then, we applied a machine learning algorithm to develop a predictive diagnostic and a prognostic model using cell-free DNA (cfDNA) samples from a cohort of 801 patients with CRC and 1021 normal controls. The obtained diagnostic prediction model discriminated patients with CRC from normal controls with high accuracy (area under curve = 0.96). The prognostic prediction model also effectively predicted the prognosis and survival of patients with CRC (P < 0.001). In addition, we generated a ctDNA-based molecular classification of CRC using an unsupervised clustering method and obtained two subgroups of patients with CRC with significantly different overall survival (P = 0.011 in validation cohort). Last, we found that a single ctDNA methylation marker, cg10673833, could yield high sensitivity (89.7%) and specificity (86.8%) for detection of CRC and precancerous lesions in a high-risk population of 1493 participants in a prospective cohort study. Together, our findings showed the value of ctDNA methylation markers in the diagnosis, surveillance, and prognosis of CRC.
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Affiliation(s)
- Huiyan Luo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Qi Zhao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Wei Wei
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Lianghong Zheng
- Guangzhou Youze Biological Pharmaceutical Technology Company Ltd., Guangzhou 510005, P.R. China
| | - Shaohua Yi
- Huazhong University of Science and Technology Tongji Medical College, Wuhan 430030, P. R. China
| | - Gen Li
- Guangzhou Women and Children’s Medical Center, Guangzhou 510623, P. R. China
| | - Wenqiu Wang
- Shanghai General Hospital, Shanghai 200080, P. R. China
| | - Hui Sheng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Hengying Pu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Haiyu Mo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Zhixiang Zuo
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Zexian Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Chaofeng Li
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Chuanbo Xie
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Zhaolei Zeng
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Weimin Li
- Molecular Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
| | - Xiaoke Hao
- Department of Clinical Laboratory Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, P. R. China
| | - Yuying Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Sumei Cao
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Wanli Liu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Sarah Gibson
- Guangzhou Women and Children’s Medical Center, Guangzhou 510623, P. R. China
| | - Kang Zhang
- Molecular Medicine Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China
- Faculty of Medicine, Macau University of Science and Technology, Macau 999078, P. R. China
| | - Guoliang Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
| | - Rui-hua Xu
- Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, P. R. China
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50
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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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