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Kalra A, Meltzer SJ. The Role of DNA Methylation in Gastrointestinal Disease: An Expanded Review of Malignant and Nonmalignant Gastrointestinal Diseases. Gastroenterology 2025; 168:245-266. [PMID: 38971197 PMCID: PMC11698954 DOI: 10.1053/j.gastro.2024.07.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 06/20/2024] [Accepted: 07/01/2024] [Indexed: 07/08/2024]
Abstract
Esophageal, colorectal, pancreatic, hepatocellular, and gastric cancer together impact millions of patients worldwide each year, with high overall mortality rates, and are increasing in incidence. Additionally, premalignant gastrointestinal diseases, such as Barrett's esophagus and inflammatory bowel disease, are also increasing in incidence. However, involvement of aberrant DNA methylation in these diseases is incompletely understood, especially given recent research advancements in this field. Here, we review knowledge of this epigenetic mechanism in gastrointestinal preneoplasia and neoplasia, considering mechanisms of action, genetic and environmental factors, and 5'-C-phosphate-G-3' island methylator phenotype. We also highlight developments in translational research, focusing on genomic-wide data, methylation-based biomarkers and diagnostic tests, machine learning, and therapeutic epigenetic strategies.
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Affiliation(s)
- Andrew Kalra
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania
| | - Stephen J Meltzer
- Division of Gastroenterology and Hepatology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Wang Q, Ma C, Yang B, Zheng W, Liu X, Jian G. Dysregulation of DNA methylation in colorectal cancer: biomarker, immune regulation, and therapeutic potential. Int Immunopharmacol 2025; 145:113766. [PMID: 39644791 DOI: 10.1016/j.intimp.2024.113766] [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: 11/10/2024] [Revised: 11/16/2024] [Accepted: 11/30/2024] [Indexed: 12/09/2024]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide, with morbidity and mortality ranking third and second among all cancers, respectively. As a result of a sequence of genetic and DNA methylation alterations that gradually accumulate in the healthy colonic epithelium, colorectal adenomas and invasive adenocarcinomas eventually give rise to CRC. Global hypomethylation and promoter-specific DNA methylation are characteristics of CRC. The pathophysiological role of aberrant DNA methylation in malignant tumors has garnered significant interest in the last few decades. In addition, DNA methylation has been shown to play a critical role in influencing immune cell function and tumor immune evasion. This review summarizes the most recent research on DNA methylation changes in CRC, including the role of DNA methylation-related enzymes in CRC tumorigenesis and biomarkers for diagnosis, predictive and prognostic. Besides, we focus on the emerging potential of epigenetic interventions to enhance antitumor immune responses and improve the CRC clinical practice.
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Affiliation(s)
- Qin Wang
- School of Pharmacy, Southwest Minzu University, Chengdu, China; Department of Pathology, Yong Yoo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Chen Ma
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Bin Yang
- School of Traditional Chinese Medicine, Capital Medical University, Beijing, China
| | - Wenxin Zheng
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Xinya Liu
- School of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Gu Jian
- School of Pharmacy, Southwest Minzu University, Chengdu, China
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Younesian S, Mohammadi MH, Younesian O, Momeny M, Ghaffari SH, Bashash D. DNA methylation in human diseases. Heliyon 2024; 10:e32366. [PMID: 38933971 PMCID: PMC11200359 DOI: 10.1016/j.heliyon.2024.e32366] [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: 09/24/2023] [Revised: 05/30/2024] [Accepted: 06/03/2024] [Indexed: 06/28/2024] Open
Abstract
Aberrant epigenetic modifications, particularly DNA methylation, play a critical role in the pathogenesis and progression of human diseases. The current review aims to reveal the role of aberrant DNA methylation in the pathogenesis and progression of diseases and to discuss the original data obtained from international research laboratories on this topic. In the review, we mainly summarize the studies exploring the role of aberrant DNA methylation as diagnostic and prognostic biomarkers in a broad range of human diseases, including monogenic epigenetics, autoimmunity, metabolic disorders, hematologic neoplasms, and solid tumors. The last section provides a general overview of the possibility of the DNA methylation machinery from the perspective of pharmaceutic approaches. In conclusion, the study of DNA methylation machinery is a phenomenal intersection that each of its ways can reveal the mysteries of various diseases, introduce new diagnostic and prognostic biomarkers, and propose a new patient-tailored therapeutic approach for diseases.
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Affiliation(s)
- Samareh Younesian
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
| | - Mohammad Hossein Mohammadi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
| | - Ommolbanin Younesian
- School of Medicine, Tonekabon Branch, Islamic Azad University, Tonekabon, 46841-61167 Iran
| | - Majid Momeny
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, 77030 TX, USA
| | - Seyed H. Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, 1411713135 Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, 1971653313 Iran
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Rendek T, Pos O, Duranova T, Saade R, Budis J, Repiska V, Szemes T. Current Challenges of Methylation-Based Liquid Biopsies in Cancer Diagnostics. Cancers (Basel) 2024; 16:2001. [PMID: 38893121 PMCID: PMC11171112 DOI: 10.3390/cancers16112001] [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: 04/23/2024] [Revised: 05/13/2024] [Accepted: 05/16/2024] [Indexed: 06/21/2024] Open
Abstract
In current clinical practice, effective cancer testing and screening paradigms are limited to specific types of cancer, exhibiting varying efficiency, acceptance, and adherence. Cell-free DNA (cfDNA) methylation profiling holds promise in providing information about the presence of malignity regardless of its type and location while leveraging blood-based liquid biopsies as a method to obtain analytical samples. However, technical difficulties, costs and challenges resulting from biological variations, tumor heterogeneity, and exogenous factors persist. This method exploits the mechanisms behind cfDNA release but faces issues like fragmentation, low concentrations, and high background noise. This review explores cfDNA methylation's origins, means of detection, and profiling for cancer diagnostics. The critical evaluation of currently available multi-cancer early detection methods (MCEDs) as well as tests targeting single genes, emphasizing their potential and limits to refine strategies for early cancer detection, are explained. The current methodology limitations, workflows, comparisons of clinically approved liquid biopsy-based methylation tests for cancer, their utilization in companion diagnostics as well as the biological limitations of the epigenetics approach are discussed, aiming to help healthcare providers as well as researchers to orient themselves in this increasingly complex and evolving field of diagnostics.
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Affiliation(s)
- Tomas Rendek
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Ondrej Pos
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | | | - Rami Saade
- 2nd Department of Gynaecology and Obstetrics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Jaroslav Budis
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
| | - Vanda Repiska
- Institute of Medical Biology, Genetics and Clinical Genetics, Faculty of Medicine, Comenius University, 811 08 Bratislava, Slovakia;
| | - Tomas Szemes
- Geneton Ltd., 841 04 Bratislava, Slovakia; (O.P.); (J.B.); (T.S.)
- Comenius University Science Park, 841 04 Bratislava, Slovakia;
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Zhao N, Lai C, Wang Y, Dai S, Gu H. Understanding the role of DNA methylation in colorectal cancer: Mechanisms, detection, and clinical significance. Biochim Biophys Acta Rev Cancer 2024; 1879:189096. [PMID: 38499079 DOI: 10.1016/j.bbcan.2024.189096] [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: 10/05/2023] [Revised: 02/18/2024] [Accepted: 03/13/2024] [Indexed: 03/20/2024]
Abstract
Colorectal cancer (CRC) is one of the deadliest malignancies worldwide, ranking third in incidence and second in mortality. Remarkably, early stage localized CRC has a 5-year survival rate of over 90%; in stark contrast, the corresponding 5-year survival rate for metastatic CRC (mCRC) is only 14%. Compounding this problem is the staggering lack of effective therapeutic strategies. Beyond genetic mutations, which have been identified as critical instigators of CRC initiation and progression, the importance of epigenetic modifications, particularly DNA methylation (DNAm), cannot be underestimated, given that DNAm can be used for diagnosis, treatment monitoring and prognostic evaluation. This review addresses the intricate mechanisms governing aberrant DNAm in CRC and its profound impact on critical oncogenic pathways. In addition, a comprehensive review of the various techniques used to detect DNAm alterations in CRC is provided, along with an exploration of the clinical utility of cancer-specific DNAm alterations.
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Affiliation(s)
- Ningning Zhao
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, China
| | - Chuanxi Lai
- Division of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China
| | - Yunfei Wang
- Zhejiang ShengTing Biotech. Ltd, Hangzhou 310000, China
| | - Sheng Dai
- Division of Colorectal Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310016, China.
| | - Hongcang Gu
- Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei 230031, China; Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei 230031, 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] [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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Ye J, Zhang J, Ding W. DNA methylation modulates epigenetic regulation in colorectal cancer diagnosis, prognosis and precision medicine. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:34-53. [PMID: 38464391 PMCID: PMC10918240 DOI: 10.37349/etat.2024.00203] [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: 09/25/2023] [Accepted: 12/11/2023] [Indexed: 03/12/2024] Open
Abstract
Colorectal cancer (CRC) is a multifaceted disease influenced by the interplay of genetic and environmental factors. The clinical heterogeneity of CRC cannot be attributed exclusively to genetic diversity and environmental exposures, and epigenetic markers, especially DNA methylation, play a critical role as key molecular markers of cancer. This review compiles a comprehensive body of evidence underscoring the significant involvement of DNA methylation modifications in the pathogenesis of CRC. Moreover, this review explores the potential utility of DNA methylation in cancer diagnosis, prognostics, assessment of disease activity, and prediction of drug responses. Recognizing the impact of DNA methylation will enhance the ability to identify distinct CRC subtypes, paving the way for personalized treatment strategies and advancing precision medicine in the management of CRC.
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Affiliation(s)
- Jingxin Ye
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
- Department of Gastroenterology, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian 223800, Jiangsu Province, China
| | - Jianfeng Zhang
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
| | - Weifeng Ding
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu Province, China
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Khabbazpour M, Tat M, Karbasi A, Abyazi MA, Khodadoustan G, Heidary Z, Zaki-Dizaji M. Advances in blood DNA methylation-based assay for colorectal cancer early detection: a systematic updated review. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2024; 17:225-240. [PMID: 39308542 PMCID: PMC11413380 DOI: 10.22037/ghfbb.v17i3.2978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Accepted: 07/04/2024] [Indexed: 09/25/2024]
Abstract
Aim A systematic review was conducted to summarize the methylated circulating tumor DNA (ctDNA) markers reported over the last decade for early detection of colorectal cancer (CRC) and to identify the main technical challenges that are impeding their clinical implementation. Background CRC is a major cause of cancer deaths worldwide, but early detection is key for successful treatment. Non-invasive methods such as methylated ctDNA testing show promise for improving detection and monitoring of CRC. Methods A comprehensive search was performed using Web of Science, PubMed, and Scopus up to December 30, 2023, limited to articles published in the last 10 years (after 2012), while including advanced adenoma/stage 0 or stage I/II samples in biomarker validation. Results After identifying 694 articles, removing duplicates and screening titles, abstracts, and full texts, a total of 62 articles were found to meet the inclusion criteria. Among the single biomarkers, MYO1-G, SEPT9, SDC2, and JAM3 revealed the highest sensitivity for polyps and stage I/II CRC. For multi-biomarkers with suitable sensitivity, combinations of SFRP1, SFRP2, SDC2, PRIMA1, or ALX4, BMP3, NPTX2, RARB, SDC2, SEPT9, VIM or ZFHX4, ZNF334, ELOVL2, UNC5C, LOC146880, SFMBT2, GFRA1 were identified for polyps and stage I/II CRC. Conclusion Enhancing sensitivity and specificity of molecular screening methods is crucial for improving CRC detection. Identifying a select few valuable biomarkers is key to reducing costs, despite challenges posed by low ctDNA levels in plasma, particularly in early-stage cancers.
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Affiliation(s)
- Milad Khabbazpour
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Masoud Tat
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ashraf Karbasi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Abyazi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Ghazal Khodadoustan
- Department of Cell and Molecular Biology and Microbiology, Faculty of biological science and technology, University of Isfahan, Isfahan, Iran
| | - Zohreh Heidary
- Vali-e-Asr Reproductive Health Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Majid Zaki-Dizaji
- Human Genetics Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Casula G, Lai S, Loi E, Moi L, Zavattari P, Bonfiglio A. An innovative PCR-free approach for DNA methylation measure: An application for early colorectal cancer detection by means of an organic biosensor. SENSORS AND ACTUATORS B: CHEMICAL 2024; 398:134698. [DOI: 10.1016/j.snb.2023.134698] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Coppedè F, Bhaduri U, Stoccoro A, Nicolì V, Di Venere E, Merla G. DNA Methylation in the Fields of Prenatal Diagnosis and Early Detection of Cancers. Int J Mol Sci 2023; 24:11715. [PMID: 37511475 PMCID: PMC10380460 DOI: 10.3390/ijms241411715] [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: 05/31/2023] [Revised: 07/10/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
The central objective of the metamorphosis of discovery science into biomedical applications is to serve the purpose of patients and curtail the global disease burden. The journey from the discovery of DNA methylation (DNAm) as a biological process to its emergence as a diagnostic tool is one of the finest examples of such metamorphosis and has taken nearly a century. Particularly in the last decade, the application of DNA methylation studies in the clinic has been standardized more than ever before, with great potential to diagnose a multitude of diseases that are associated with a burgeoning number of genes with this epigenetic alteration. Fetal DNAm detection is becoming useful for noninvasive prenatal testing, whereas, in very preterm infants, DNAm is also shown to be a potential biological indicator of prenatal risk factors. In the context of cancer, liquid biopsy-based DNA-methylation profiling is offering valuable epigenetic biomarkers for noninvasive early-stage diagnosis. In this review, we focus on the applications of DNA methylation in prenatal diagnosis for delivering timely therapy before or after birth and in detecting early-stage cancers for better clinical outcomes. Furthermore, we also provide an up-to-date commercial landscape of DNAm biomarkers for cancer detection and screening of cancers of unknown origin.
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Affiliation(s)
- Fabio Coppedè
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
- Interdepartmental Research Center of Biology and Pathology of Aging, University of Pisa, 56126 Pisa, Italy
| | - Utsa Bhaduri
- Laboratory of Regulatory & Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Andrea Stoccoro
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
| | - Vanessa Nicolì
- Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, 56126 Pisa, Italy
| | - Eleonora Di Venere
- Department of Molecular Medicine & Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
| | - Giuseppe Merla
- Laboratory of Regulatory & Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, 71013 Foggia, Italy
- Department of Molecular Medicine & Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy
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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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Tulsyan S, Aftab M, Sisodiya S, Khan A, Chikara A, Tanwar P, Hussain S. Molecular basis of epigenetic regulation in cancer diagnosis and treatment. Front Genet 2022; 13:885635. [PMID: 36092905 PMCID: PMC9449878 DOI: 10.3389/fgene.2022.885635] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 07/19/2022] [Indexed: 02/01/2023] Open
Abstract
The global cancer cases and mortality rates are increasing and demand efficient biomarkers for accurate screening, detection, diagnosis, and prognosis. Recent studies have demonstrated that variations in epigenetic mechanisms like aberrant promoter methylation, altered histone modification and mutations in ATP-dependent chromatin remodelling complexes play an important role in the development of carcinogenic events. However, the influence of other epigenetic alterations in various cancers was confirmed with evolving research and the emergence of high throughput technologies. Therefore, alterations in epigenetic marks may have clinical utility as potential biomarkers for early cancer detection and diagnosis. In this review, an outline of the key epigenetic mechanism(s), and their deregulation in cancer etiology have been discussed to decipher the future prospects in cancer therapeutics including precision medicine. Also, this review attempts to highlight the gaps in epigenetic drug development with emphasis on integrative analysis of epigenetic biomarkers to establish minimally non-invasive biomarkers with clinical applications.
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Affiliation(s)
- Sonam Tulsyan
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Mehreen Aftab
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
| | - Sandeep Sisodiya
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Asiya Khan
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
| | - Atul Chikara
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- Symbiosis School of Biological Sciences, Symbiosis International (Deemed University), Pune, India
| | - Pranay Tanwar
- Laboratory Oncology Unit, Dr. B. R. A. Institute Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, India
- *Correspondence: Showket Hussain, ; Pranay Tanwar,
| | - Showket Hussain
- Division of Cellular and Molecular Diagnostics (Molecular Biology Group), ICMR- National Institute of Cancer Prevention and Research, Noida, India
- *Correspondence: Showket Hussain, ; Pranay Tanwar,
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Mauri G, Vitiello PP, Sogari A, Crisafulli G, Sartore-Bianchi A, Marsoni S, Siena S, Bardelli A. Liquid biopsies to monitor and direct cancer treatment in colorectal cancer. Br J Cancer 2022; 127:394-407. [PMID: 35264786 PMCID: PMC9346106 DOI: 10.1038/s41416-022-01769-8] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 02/02/2022] [Accepted: 02/17/2022] [Indexed: 12/15/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent and deadly cancers worldwide. Despite recent improvements in treatment and prevention, most of the current therapeutic options are weighted by side effects impacting patients' quality of life. Better patient selection towards systemic treatments represents an unmet clinical need. The recent multidisciplinary and molecular advancements in the treatment of CRC patients demand the identification of efficient biomarkers allowing to personalise patient care. Currently, core tumour biopsy specimens represent the gold-standard biological tissue to identify such biomarkers. However, technical feasibility, tumour heterogeneity and cancer evolution are major limitations of this single-snapshot approach. Genotyping circulating tumour DNA (ctDNA) has been addressed as potentially overcoming such limitations. Indeed, ctDNA has been retrospectively demonstrated capable of identifying minimal residual disease post-surgery and post-adjuvant treatment, as well as spotting druggable molecular alterations for tailoring treatments in metastatic disease. In this review, we summarise the available evidence on ctDNA applicability in CRC. Then, we review ongoing clinical trials assessing how liquid biopsy can be used interventionally to guide therapeutic choice in localised, locally advanced and metastatic CRC. Finally, we discuss how its widespread could transform CRC patients' management, dissecting its limitations while suggesting improvement strategies.
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Affiliation(s)
- Gianluca Mauri
- IFOM-FIRC Institute of Molecular Oncology, Milan, Italy
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Pietro Paolo Vitiello
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Alberto Sogari
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Giovanni Crisafulli
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy
| | - Andrea Sartore-Bianchi
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
| | | | - Salvatore Siena
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, 20162, Milan, Italy
| | - Alberto Bardelli
- Candiolo Cancer Institute, FPO-IRCCS, 10060, Candiolo, TO, Italy.
- Department of Oncology, University of Torino, 10060, Candiolo, TO, Italy.
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14
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Sattar RSA, Verma R, Nimisha, Kumar A, Dar GM, Apurva, Sharma AK, Kumari I, Ahmad E, Ali A, Mahajan B, Saluja SS. Diagnostic and prognostic biomarkers in colorectal cancer and the potential role of exosomes in drug delivery. Cell Signal 2022; 99:110413. [PMID: 35907519 DOI: 10.1016/j.cellsig.2022.110413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/03/2022]
Abstract
Colorectal cancer (CRC) is third most common cancer with second most common cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNA, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.
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Affiliation(s)
- Real Sumayya Abdul Sattar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Renu Verma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ghulam Mehdi Dar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Apurva
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Indu Kumari
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ejaj Ahmad
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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15
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Yuan RQ, Zhao H, Wang Y, Song K, Yang J, He W, Miao DZ, Wang Q, Jia YH. SEPTIN9-SDC2-VIM methylation signature as a biomarker for the early diagnosis of colorectal cancer. Am J Cancer Res 2022; 12:3128-3140. [PMID: 35968354 PMCID: PMC9360219] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/13/2022] [Indexed: 06/15/2023] Open
Abstract
The accurate detection of colorectal cancer (CRC) at its initial stage can reduce mortality. However, the broad application of endoscopy has been limited due to the invasive procedure and patient noncompliance. Liquid biopsy with subsequent mapping of methylation in specific cell-free DNA (cfDNA) may represent an alternative approach for early diagnosis. In this study, we have developed a minimal-invasive blood-based test for detection of precancerous lesions and early-stage CRC. Using TCGA M450K methylation data, we identified candidate methylation sites with the highest Fold Change (FC) for three genes (SEPTIN9, SDC2 and VIM), which were selected from previous studies. Based on logistic regression models, we developed a 3-gene methylation signature for CRC diagnosis with high accuracy (Sensitivity =0.959, Specificity =1, AUC =0.997). Using independent public databases and data from blood samples, this model has demonstrated superior performance. The AUC was 0.919-1 and 0.905-0.916 in public tissue database for CRC and blood sample data, respectively. Thus, our proposed 3-gene methylation signature has a more reliable performance than other methods. Furthermore, signal enhancement effect of 3-gene methylation signature can improve the accuracy of early diagnosis for CRC, which demonstrates the potential for clinical application.
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Affiliation(s)
- Rong-Qiang Yuan
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical UniversityHarbin 150086, Heilongjiang, China
| | - Hui Zhao
- The First Affiliated Hospital, Harbin Medical UniversityHarbin 150001, Heilongjiang, China
| | - Yan Wang
- Harbin Medical University Cancer Hospital Colorectal Cancer CenterHarbin 150086, Heilongjiang, China
| | - Kai Song
- Zhuhai Interventional Medical Center, Zhuhai Precision Medical Center, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Jinan UniversityZhuhai 519000, Guangdong, China
| | - Jia Yang
- Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical UniversityHarbin 150086, Heilongjiang, China
| | - Wei He
- Harbin Medical University Cancer Hospital Colorectal Cancer CenterHarbin 150086, Heilongjiang, China
| | - Da-Zhuang Miao
- Harbin Medical University Cancer Hospital Colorectal Cancer CenterHarbin 150086, Heilongjiang, China
| | - Qi Wang
- Harbin Medical University Cancer Hospital Colorectal Cancer CenterHarbin 150086, Heilongjiang, China
| | - Yun-He Jia
- Harbin Medical University Cancer Hospital Colorectal Cancer CenterHarbin 150086, Heilongjiang, China
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16
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Ceccon C, Angerilli V, Rasola C, Procaccio L, Sabbadin M, Bergamo F, Malapelle U, Lonardi S, Fassan M. Microsatellite Instable Colorectal Adenocarcinoma Diagnostics: The Advent of Liquid Biopsy Approaches. Front Oncol 2022; 12:930108. [PMID: 35837109 PMCID: PMC9273960 DOI: 10.3389/fonc.2022.930108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Accepted: 05/30/2022] [Indexed: 11/24/2022] Open
Abstract
The introduction of immunotherapy has revolutionized the oncological targeted therapy paradigm. Microsatellite instability (MSI) identifies a subgroup of colorectal cancers (CRCs) which respond to treatment with immune checkpoint inhibitors. Tissue biopsy is currently the gold standard for the assessment of MSI/Mismatch Repair deficiency (MMRd) by means immunohistochemistry or molecular assays. However, the application of liquid biopsy in the clinic may help to overcome several limitations of tissue analysis and may provide great benefit to the diagnostic scenario and therapeutic decision-making process. In the context of MSI/MMRd CRC, the use of liquid biopsy may allow to establish MSI/MMR status if tissue sampling cannot be performed or in case of discordant tissue biopsies. Liquid biopsy may also become a powerful tool to monitor treatment response and the onset resistance to immunotherapy over time and to stratify of MSI/MMRd patients according to their risk of relapse and metastases. The aim of this review is to summarize the main technical aspects and clinical applications, the benefits, and limitations of the use of liquid biopsy in MSI/MMRd colorectal cancer patients.
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Affiliation(s)
- Carlotta Ceccon
- Department of Medicine (DIMED), University of Padua, Padua, Italy
| | | | - Cosimo Rasola
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padua, Italy
| | | | | | | | - Umberto Malapelle
- Department of Public Health, University of Naples Federico II, Naples, Italy
| | - Sara Lonardi
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
| | - Matteo Fassan
- Department of Medicine (DIMED), University of Padua, Padua, Italy
- Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy
- *Correspondence: Matteo Fassan,
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17
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Santaló J, Berdasco M. Ethical implications of epigenetics in the era of personalized medicine. Clin Epigenetics 2022; 14:44. [PMID: 35337378 PMCID: PMC8953972 DOI: 10.1186/s13148-022-01263-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Accepted: 03/17/2022] [Indexed: 11/10/2022] Open
Abstract
Given the increasing research activity on epigenetics to monitor human diseases and its connection with lifestyle and environmental expositions, the field of epigenetics has attracted a great deal of interest also at the ethical and societal level. In this review, we will identify and discuss current ethical, legal and social issues of epigenetics research in the context of personalized medicine. The review covers ethical aspects such as how epigenetic information should impact patient autonomy and the ability to generate an intentional and voluntary decision, the measures of data protection related to privacy and confidentiality derived from epigenome studies (e.g., risk of discrimination, patient re-identification and unexpected findings) or the debate in the distribution of responsibilities for health (i.e., personal versus public responsibilities). We pay special attention to the risk of social discrimination and stigmatization as a consequence of inferring information related to lifestyle and environmental exposures potentially contained in epigenetic data. Furthermore, as exposures to the environment and individual habits do not affect all populations equally, the violation of the principle of distributive justice in the access to the benefits of clinical epigenetics is discussed. In this regard, epigenetics represents a great opportunity for the integration of public policy measures aimed to create healthier living environments. Whether these public policies will coexist or, in contrast, compete with strategies reinforcing the personalized medicine interventions needs to be considered. The review ends with a reflection on the main challenges in epigenetic research, some of them in a technical dimension (e.g., assessing causality or establishing reference epigenomes) but also in the ethical and social sphere (e.g., risk to add an epigenetic determinism on top of the current genetic one). In sum, integration into life science investigation of social experiences such as exposure to risk, nutritional habits, prejudice and stigma, is imperative to understand epigenetic variation in disease. This pragmatic approach is required to locate clinical epigenetics out of the experimental laboratories and facilitate its implementation into society.
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Affiliation(s)
- Josep Santaló
- Facultat de Biociències, Unitat de Biologia Cel·lular, Universitat Autònoma de Barcelona, Barcelona, Spain
| | - María Berdasco
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain. .,Epigenetic Therapies Group, Experimental and Clinical Hematology Program (PHEC), Josep Carreras Leukaemia Research Institute, Badalona, Barcelona, Catalonia, Spain.
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18
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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: 70] [Impact Index Per Article: 23.3] [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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19
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Ionica E, Gaina G, Tica M, Chifiriuc MC, Gradisteanu-Pircalabioru G. Contribution of Epithelial and Gut Microbiome Inflammatory Biomarkers to the Improvement of Colorectal Cancer Patients' Stratification. Front Oncol 2022; 11:811486. [PMID: 35198435 PMCID: PMC8859258 DOI: 10.3389/fonc.2021.811486] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/20/2021] [Indexed: 12/24/2022] Open
Abstract
In order to ensure that primary endpoints of clinical studies are attained, the patients' stratification is an important aspect. Selection criteria include age, gender, and also specific biomarkers, such as inflammation scores. These criteria are not sufficient to achieve a straightforward selection, however, in case of multifactorial diseases, with unknown or partially identified mechanisms, occasionally including host factors, and the microbiome. In these cases, the efficacy of interventions is difficult to predict, and as a result, the selection of subjects is often random. Colorectal cancer (CRC) is a highly heterogeneous disease, with variable clinical features, outcomes, and response to therapy; the CRC onset and progress involves multiple sequential steps with accumulation of genetic alterations, namely, mutations, gene amplification, and epigenetic changes. The gut microbes, either eubiotic or dysbiotic, could influence the CRC evolution through a complex and versatile crosstalk with the intestinal and immune cells, permanently changing the tumor microenvironment. There have been significant advances in the development of personalized approaches for CRC screening, treatment, and potential prevention. Advances in molecular techniques bring new criteria for patients' stratification-mutational analysis at the time of diagnosis to guide treatment, for example. Gut microbiome has emerged as the main trigger of gut mucosal homeostasis. This may impact cancer susceptibility through maintenance of the epithelial/mucus barrier and production of protective metabolites, such as short-chain fatty acids (SCFAs) via interactions with the hosts' diet and metabolism. Microbiome dysbiosis leads to the enrichment of cancer-promoting bacterial populations, loss of protective populations or maintaining an inflammatory chronic state, all of which contribute to the development and progression of CRC. Meanwhile, variations in patient responses to anti-cancer immuno- and chemotherapies were also linked to inter-individual differences in intestine microbiomes. The authors aim to highlight the contribution of epithelial and gut microbiome inflammatory biomarkers in the improvement of CRC patients' stratification towards a personalized approach of early diagnosis and treatment.
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Affiliation(s)
- Elena Ionica
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
| | - Gisela Gaina
- Laboratory of Cell Biology, Neuroscience and Experimental Miology, Victor Babes National Institute of Pathology, Bucharest, Romania
| | - Mihaela Tica
- Bucharest Emergency University Hospital, Bucharest, Romania
| | - Mariana-Carmen Chifiriuc
- Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Bucharest, Bucharest, Romania
- Biological Science Division, Romanian Academy of Sciences, Bucharest, Romania
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Almeida-Lousada H, Mestre A, Ramalhete S, Price AJ, de Mello RA, Marreiros AD, Neves RPD, Castelo-Branco P. Screening for Colorectal Cancer Leading into a New Decade: The "Roaring '20s" for Epigenetic Biomarkers? Curr Oncol 2021; 28:4874-4893. [PMID: 34898591 PMCID: PMC8628779 DOI: 10.3390/curroncol28060411] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/12/2021] [Accepted: 11/17/2021] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) has an important bearing (top five) on cancer incidence and mortality in the world. The etiology of sporadic CRC is related to the accumulation of genetic and epigenetic alterations that result in the appearance of cancer hallmarks such as abnormal proliferation, evasion of immune destruction, resistance to apoptosis, replicative immortality, and others, contributing to cancer promotion, invasion, and metastasis. It is estimated that, each year, at least four million people are diagnosed with CRC in the world. Depending on CRC staging at diagnosis, many of these patients die, as CRC is in the top four causes of cancer death in the world. New and improved screening tests for CRC are needed to detect the disease at an early stage and adopt patient management strategies to decrease the death toll. The three pillars of CRC screening are endoscopy, radiological imaging, and molecular assays. Endoscopic procedures comprise traditional colonoscopy, and more recently, capsule-based endoscopy. The main imaging modality remains Computed Tomography (CT) of the colon. Molecular approaches continue to grow in the diversity of biomarkers and the sophistication of the technologies deployed to detect them. What started with simple fecal occult blood tests has expanded to an armamentarium, including mutation detection and identification of aberrant epigenetic signatures known to be oncogenic. Biomarker-based screening methods have critical advantages and are likely to eclipse the classical modalities of imaging and endoscopy in the future. For example, imaging methods are costly and require highly specialized medical personnel. In the case of endoscopy, their invasiveness limits compliance from large swaths of the population, especially those with average CRC risk. Beyond mere discomfort and fear, there are legitimate iatrogenic concerns associated with endoscopy. The risks of perforation and infection make endoscopy best suited for a confirmatory role in cases where there are positive results from other diagnostic tests. Biomarker-based screening methods are largely non-invasive and are growing in scope. Epigenetic biomarkers, in particular, can be detected in feces and blood, are less invasive to the average-risk patient, detect early-stage CRC, and have a demonstrably superior patient follow-up. Given the heterogeneity of CRC as it evolves, optimal screening may require a battery of blood and stool tests, where each can leverage different pathways perturbed during carcinogenesis. What follows is a comprehensive, systematic review of the literature pertaining to the screening and diagnostic protocols used in CRC. Relevant articles were retrieved from the PubMed database using keywords including: "Screening", "Diagnosis", and "Biomarkers for CRC". American and European clinical trials in progress were included as well.
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Affiliation(s)
- Hélder Almeida-Lousada
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - André Mestre
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Sara Ramalhete
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Aryeh J. Price
- School of Law, University of California, Berkeley, CA 94704, USA;
| | - Ramon Andrade de Mello
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Division of Medical Oncology, Escola Paulista de Medicina, Federal University of São Paulo (UNIFESP), São Paulo 04037-004, Brazil
- Precision Oncology & Health Economics Group (ONCOPRECH), Post-Graduation Program in Medicine, Nine of July University (UNINOVE), São Paulo 01525-000, Brazil
| | - Ana D. Marreiros
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
| | - Ricardo Pires das Neves
- CNC—Center for Neuroscience and Cell Biology, CIBB—Centre for Innovative Biomedicine and Biotechnology, University of Coimbra, 3004-517 Coimbra, Portugal
- IIIUC—Institute of Interdisciplinary Research, University of Coimbra, 3004-517 Coimbra, Portugal
- Correspondence: (R.P.d.N.); (P.C.-B.); Tel.: +351-231-249-170 (R.P.d.N.); +351-289-800-100 (ext. 7813) (P.C.-B.)
| | - Pedro Castelo-Branco
- Faculty of Medicine and Biomedical Sciences (FMCB), Campus de Gambelas, University of Algarve, 8005-139 Faro, Portugal; (H.A.-L.); (A.M.); (S.R.); (R.A.d.M.); (A.D.M.)
- Algarve Biomedical Center Research Institute (ABC-RI), 8005-139 Faro, Portugal
- Champalimaud Research Program, Champalimaud Center for the Unknown, 1400-038 Lisbon, Portugal
- Correspondence: (R.P.d.N.); (P.C.-B.); Tel.: +351-231-249-170 (R.P.d.N.); +351-289-800-100 (ext. 7813) (P.C.-B.)
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21
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DNA Methylation and Type 2 Diabetes: Novel Biomarkers for Risk Assessment? Int J Mol Sci 2021; 22:ijms222111652. [PMID: 34769081 PMCID: PMC8584054 DOI: 10.3390/ijms222111652] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/25/2021] [Accepted: 10/25/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.
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22
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Mazouji O, Ouhajjou A, Incitti R, Mansour H. Updates on Clinical Use of Liquid Biopsy in Colorectal Cancer Screening, Diagnosis, Follow-Up, and Treatment Guidance. Front Cell Dev Biol 2021; 9:660924. [PMID: 34150757 PMCID: PMC8213391 DOI: 10.3389/fcell.2021.660924] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 03/30/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide, being the third most diagnosed in the world and the second deadliest. Solid biopsy provides an essential guide for the clinical management of patients with colorectal cancer; however, this method presents several limitations, in particular invasiveness, and cannot be used repeatedly. Recently, clinical research directed toward the use of liquid biopsy, as an alternative tool to solid biopsy, showed significant promise in several CRC clinical applications, as (1) detect CRC patients at early stage, (2) make treatment decision, (3) monitor treatment response, (4) predict relapses and metastases, (5) unravel tumor heterogeneity, and (6) detect minimal residual disease. The purpose of this short review is to describe the concept, the characteristics, the genetic components, and the technologies used in liquid biopsy in the context of the management of colorectal cancer, and finally we reviewed gene alterations, recently described in the literature, as promising potential biomarkers that may be specifically used in liquid biopsy tests.
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Affiliation(s)
- Omayma Mazouji
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
| | | | - Roberto Incitti
- Computational Bioscience Research Center (CBRC), King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia
| | - Hicham Mansour
- GES-LCM2E, FPN, Mohamed First University, Oujda, Morocco
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23
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Nepali K, Liou JP. Recent developments in epigenetic cancer therapeutics: clinical advancement and emerging trends. J Biomed Sci 2021; 28:27. [PMID: 33840388 PMCID: PMC8040241 DOI: 10.1186/s12929-021-00721-x] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/29/2021] [Indexed: 12/13/2022] Open
Abstract
Epigenetic drug discovery field has evidenced significant advancement in the recent times. A plethora of small molecule inhibitors have progressed to clinical stage investigations and are being explored exhaustively to ascertain conclusive benefits in diverse malignancies. Literature precedents indicates that substantial amount of efforts were directed towards the use of epigenetic tools in monotherapy as well as in combination regimens at the clinical level, however, the preclinical/preliminary explorations were inclined towards the identification of prudent approaches that can leverage the anticancer potential of small molecule epigenetic inhibitors as single agents only. This review article presents an update of FDA approved epigenetic drugs along with the epigenetic inhibitors undergoing clinical stage investigations in different cancer types. A detailed discussion of the pragmatic strategies that are expected to steer the progress of the epigenetic therapy through the implementation of emerging approaches such as PROTACS and CRISPR/Cas9 along with logical ways for scaffold fabrication to selectively approach the enzyme isoforms in pursuit of garnering amplified antitumor effects has been covered. In addition, the compilation also presents the rational strategies for the construction of multi-targeting scaffold assemblages employing previously identified pharmacophores as potential alternatives to the combination therapy.
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Affiliation(s)
- Kunal Nepali
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan
| | - Jing-Ping Liou
- School of Pharmacy, College of Pharmacy, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
- Biomedical Commercialization Center, Taipei Medical University, Taipei, 11031, Taiwan.
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24
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Integrated approaches for precision oncology in colorectal cancer: The more you know, the better. Semin Cancer Biol 2021; 84:199-213. [PMID: 33848627 DOI: 10.1016/j.semcancer.2021.04.007] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 03/30/2021] [Accepted: 04/07/2021] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies accounting for approximately 10 % of worldwide cancer incidence and mortality. While early-stage CRC is mainly a preventable and curable disease, metastatic colorectal cancer (mCRC) remains an unmet clinical need. Moreover, about 25 % of CRC cases are diagnosed only at the metastatic stage. Despite the extensive molecular and functional knowledge on this disease, systemic therapy for mCRC still relies on traditional 5-fluorouracil (5-FU)-based chemotherapy regimens. On the other hand, targeted therapies and immunotherapy have shown effectiveness only in a limited subset of patients. For these reasons, there is a growing need to define the molecular and biological landscape of individual patients to implement novel, rationally driven, tailored therapies. In this review, we explore current and emerging approaches for CRC management such as genomic, transcriptomic and metabolomic analysis, the use of liquid biopsies and the implementation of patients' preclinical avatars. In particular, we discuss the contribution of each of these tools in elucidating patient specific features, with the aim of improving our ability in advancing the diagnosis and treatment of colorectal tumors.
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25
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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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26
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Traversi D, Pulliero A, Izzotti A, Franchitti E, Iacoviello L, Gianfagna F, Gialluisi A, Izzi B, Agodi A, Barchitta M, Calabrò GE, Hoxhaj I, Sassano M, Sbrogiò LG, Del Sole A, Marchiori F, Pitini E, Migliara G, Marzuillo C, De Vito C, Tamburro M, Sammarco ML, Ripabelli G, Villari P, Boccia S. Precision Medicine and Public Health: New Challenges for Effective and Sustainable Health. J Pers Med 2021; 11:135. [PMID: 33669364 PMCID: PMC7920275 DOI: 10.3390/jpm11020135] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 02/11/2021] [Accepted: 02/14/2021] [Indexed: 02/06/2023] Open
Abstract
The development of high-throughput omics technologies represents an unmissable opportunity for evidence-based prevention of adverse effects on human health. However, the applicability and access to multi-omics tests are limited. In Italy, this is due to the rapid increase of knowledge and the high levels of skill and economic investment initially necessary. The fields of human genetics and public health have highlighted the relevance of an implementation strategy at a national level in Italy, including integration in sanitary regulations and governance instruments. In this review, the emerging field of public health genomics is discussed, including the polygenic scores approach, epigenetic modulation, nutrigenomics, and microbiomes implications. Moreover, the Italian state of implementation is presented. The omics sciences have important implications for the prevention of both communicable and noncommunicable diseases, especially because they can be used to assess the health status during the whole course of life. An effective population health gain is possible if omics tools are implemented for each person after a preliminary assessment of effectiveness in the medium to long term.
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Affiliation(s)
- Deborah Traversi
- Department of Public Health and Pediatrics, University of Torino, Piazza Polonia 94, 10126 Torino, Italy;
| | - Alessandra Pulliero
- Department of Health Sciences School of Medicine, University of Genoa, 16132 Genova, Italy;
| | - Alberto Izzotti
- Department of Experimental Medicine, University of Genoa, 16132 Genova, Italy;
- IRCCS Ospedale Policlinico San Martino, 161632 Genova, Italy
| | - Elena Franchitti
- Department of Public Health and Pediatrics, University of Torino, Piazza Polonia 94, 10126 Torino, Italy;
| | - Licia Iacoviello
- Research Center in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (L.I.); (F.G.)
- Department of Epidemiology and Prevention, IRCCS NEUROMED, 86077 Pozzilli, Italy; (A.G.); (B.I.)
| | - Francesco Gianfagna
- Research Center in Epidemiology and Preventive Medicine (EPIMED), Department of Medicine and Surgery, University of Insubria, 21100 Varese, Italy; (L.I.); (F.G.)
- Mediterranea Cardiocentro, 80122 Napoli, Italy
| | - Alessandro Gialluisi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, 86077 Pozzilli, Italy; (A.G.); (B.I.)
| | - Benedetta Izzi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, 86077 Pozzilli, Italy; (A.G.); (B.I.)
| | - Antonella Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy; (A.A.); (M.B.)
| | - Martina Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy; (A.A.); (M.B.)
| | - Giovanna Elisa Calabrò
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.E.C.); (I.H.); (M.S.); (S.B.)
| | - Ilda Hoxhaj
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.E.C.); (I.H.); (M.S.); (S.B.)
| | - Michele Sassano
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.E.C.); (I.H.); (M.S.); (S.B.)
| | - Luca Gino Sbrogiò
- Dipartimento di Prevenzione, Az. ULSS3 Serenissima, 30174 Venezia, Italy;
| | | | | | - Erica Pitini
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Roma, Italy; (E.P.); (G.M.); (C.M.); (C.D.V.); (P.V.)
| | - Giuseppe Migliara
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Roma, Italy; (E.P.); (G.M.); (C.M.); (C.D.V.); (P.V.)
| | - Carolina Marzuillo
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Roma, Italy; (E.P.); (G.M.); (C.M.); (C.D.V.); (P.V.)
| | - Corrado De Vito
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Roma, Italy; (E.P.); (G.M.); (C.M.); (C.D.V.); (P.V.)
| | - Manuela Tamburro
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, 86100 Campobasso, Italy; (M.T.); (M.L.S.); (G.R.)
| | - Michela Lucia Sammarco
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, 86100 Campobasso, Italy; (M.T.); (M.L.S.); (G.R.)
| | - Giancarlo Ripabelli
- Department of Medicine and Health Sciences “Vincenzo Tiberio”, University of Molise, 86100 Campobasso, Italy; (M.T.); (M.L.S.); (G.R.)
| | - Paolo Villari
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Roma, Italy; (E.P.); (G.M.); (C.M.); (C.D.V.); (P.V.)
| | - Stefania Boccia
- Section of Hygiene, University Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Roma, Italy; (G.E.C.); (I.H.); (M.S.); (S.B.)
- Department of Woman and Child Health and Public Health-Public Health Area, Fondazione Policlinico Universitario A. Gemelli IRCCS, 00168 Roma, Italy
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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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28
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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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29
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Leal A, Sidransky D, Brait M. Tissue and Cell-Free DNA-Based Epigenomic Approaches for Cancer Detection. Clin Chem 2020; 66:105-116. [PMID: 31843869 DOI: 10.1373/clinchem.2019.303594] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Accepted: 11/01/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND Over 9 million people die of cancer each year worldwide, reflecting the unmet need for effective biomarkers for both cancer diagnosis and prognosis. Cancer diagnosis is complex because the majority of malignant tumors present with long periods of latency and lack of clinical presentation at early stages. During carcinogenesis, premalignant cells experience changes in their epigenetic landscapes, such as differential DNA methylation, histone modifications, nucleosome positioning, and higher orders of chromatin changes that confer growth advantage and contribute to determining the biologic phenotype of human cancers. CONTENT Recent progress in microarray platforms and next-generation sequencing approaches has allowed the characterization of abnormal epigenetic patterns genome wide in a large number of cancer cases. The sizable amount of processed data also comes with challenges regarding data management and assessment for effective biomarker exploration to be further applied in prospective clinical trials. Epigenetics-based single or panel tests of genes are being explored for clinical management to fulfill unmet needs in oncology. The advance of these tests to the clinical routine will depend on rigorous, extensive, and independent validation in well-annotated cohort of patients and commercial development of clinical routine-friendly and adequate procedures. SUMMARY In this review we discuss the analytic validation of tissue and cell-free DNA-based epigenomic approaches for early cancer detection, diagnosis, and treatment monitoring and the clinical utility of candidate epigenetic alterations applied to colorectal, glioblastoma, breast, prostate, bladder, and lung cancer management.
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Affiliation(s)
- Alessandro Leal
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD
| | - David Sidransky
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mariana Brait
- Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Otolaryngology and Head & Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
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30
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Vad-Nielsen J, Meldgaard P, Sorensen BS, Nielsen AL. Cell-free Chromatin Immunoprecipitation (cfChIP) from blood plasma can determine gene-expression in tumors from non-small-cell lung cancer patients. Lung Cancer 2020; 147:244-251. [PMID: 32759018 DOI: 10.1016/j.lungcan.2020.07.023] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 07/03/2020] [Accepted: 07/20/2020] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Lung cancer is the leading cause of cancer related death worldwide. Accurate molecular diagnostics from a tumor biopsy is paramount for correct diagnosis, treatment strategy, and prediction of outcome. However, a tumor biopsy can be misleading due to tumor heterogeneity and consecutive biopsies are rarely achievable. Importantly, tumor-specific genetic information concerning mutations and translocations, can also be obtained from liquid biopsies, e.g. blood plasma, containing cell-free DNA (cfDNA) with both systemic and tumor origin. Tumor-specific gene-expression information can also be determined from liquid biopsies using cfDNA methylation and cell-free RNA analyses. However, supplementary methodologies that can determine gene-expression patterns in lung tumors from liquid biopsies could also have diagnostic impact. MATERIALS AND METHODS We here present the method cell-free chromatin Immunoprecipitation (cfChIP), which for genes having high expression specifically in the tumor, can determine such gene-expression from blood plasma. In cfChIP cell-free nucleosomes modified with histone H3 lysine 36 tri-methylation (H3K36me3), a mark quantitatively correlated with the transcription of the underlying gene, are isolated, and associated cfDNA quantified. RESULTS We demonstrate that cfChIP from lung cancer patient blood plasma can successfully quantify the level of H3K36me3 associated with circulating cell-free nucleosomes and thereby quantify the transcriptional level of genes associated with these nucleosomes. Moreover, as a proof-of-principle we show that in blood plasma from 14 lung cancer patients, H3K36me3 cfChIP can replicate the expected higher expression of KRT6 in lung squamous cell carcinoma relative to adenocarcinoma. CONCLUSION This work shows that for genes with a high expression specifically in tumor, cfChIP can determine this gene-expression pattern from blood plasma. cfChIP is a method that determine gene-expression at the transcriptional level and accordingly can supplement cfDNA methylation and cell-free RNA analyses.
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31
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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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Li C, Zheng Y, Pu K, Zhao D, Wang Y, Guan Q, Zhou Y. A four-DNA methylation signature as a novel prognostic biomarker for survival of patients with gastric cancer. Cancer Cell Int 2020; 20:88. [PMID: 32206039 PMCID: PMC7085204 DOI: 10.1186/s12935-020-1156-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 02/26/2020] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related mortality. Lack of prognostic indicators for patient survival hinders GC treatment and survival. Methods and results Methylation profile data of patients with GC obtained from The Cancer Genome Atlas (TCGA) database were analyzed to identify methylation sites as biomarkers for GC prognosis. The cohort was divided into training and validation sets. Univariate Cox, LASSO regression,and multivariate Cox analyses revealed a close correlation of a four-DNA methylation signature as a risk score model with the overall survival of patients with GC. The survival between high-risk and low-risk score patients with GC was significantly different. Analyses of receiver operating characteristics revealed a high prognostic accuracy of the four-DNA methylation signature in patients with GC. The subgroup analysis indicated that the accuracy included that for anatomical region, histologic grade, TNM stage, pathological stage, and sex. The GC prognosis based on the four-DNA methylation signature was more precise than that based on known biomarkers. Conclusions The four-DNA methylation signature could serve as a novel independent prognostic factor that could be an important tool to predict the prognostic outcome of GC patients. This potential must be verified in a large-scale population cohort study and through basic research studies.
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Affiliation(s)
- Chunmei Li
- 1Key Laboratory for Gastrointestinal Diseases, Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,2Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ya Zheng
- 1Key Laboratory for Gastrointestinal Diseases, Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,3Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Ke Pu
- 1Key Laboratory for Gastrointestinal Diseases, Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,3Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Da Zhao
- 2Department of Oncology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- 1Key Laboratory for Gastrointestinal Diseases, Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,3Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Quanlin Guan
- 4Department of Oncology Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- 1Key Laboratory for Gastrointestinal Diseases, Gansu Province, The First Hospital of Lanzhou University, Lanzhou, China.,3Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
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33
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Loktionov A. Biomarkers for detecting colorectal cancer non-invasively: DNA, RNA or proteins? World J Gastrointest Oncol 2020; 12:124-148. [PMID: 32104546 PMCID: PMC7031146 DOI: 10.4251/wjgo.v12.i2.124] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/30/2019] [Accepted: 11/29/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is a global problem affecting millions of people worldwide. This disease is unique because of its slow progress that makes it preventable and often curable. CRC symptoms usually emerge only at advanced stages of the disease, consequently its early detection can be achieved only through active population screening, which markedly reduces mortality due to this cancer. CRC screening tests that employ non-invasively detectable biomarkers are currently being actively developed and, in most cases, samples of either stool or blood are used. However, alternative biological substances that can be collected non-invasively (colorectal mucus, urine, saliva, exhaled air) have now emerged as new sources of diagnostic biomarkers. The main categories of currently explored CRC biomarkers are: (1) Proteins (comprising widely used haemoglobin); (2) DNA (including mutations and methylation markers); (3) RNA (in particular microRNAs); (4) Low molecular weight metabolites (comprising volatile organic compounds) detectable by metabolomic techniques; and (5) Shifts in gut microbiome composition. Numerous tests for early CRC detection employing such non-invasive biomarkers have been proposed and clinically studied. While some of these studies generated promising early results, very few of the proposed tests have been transformed into clinically validated diagnostic/screening techniques. Such DNA-based tests as Food and Drug Administration-approved multitarget stool test (marketed as Cologuard®) or blood test for methylated septin 9 (marketed as Epi proColon® 2.0 CE) show good diagnostic performance but remain too expensive and technically complex to become effective CRC screening tools. It can be concluded that, despite its deficiencies, the protein (haemoglobin) detection-based faecal immunochemical test (FIT) today presents the most cost-effective option for non-invasive CRC screening. The combination of non-invasive FIT and confirmatory invasive colonoscopy is the current strategy of choice for CRC screening. However, continuing intense research in the area promises the emergence of new superior non-invasive CRC screening tests that will allow the development of improved disease prevention strategies.
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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: 491] [Impact Index Per Article: 98.2] [Reference Citation Analysis] [Abstract] [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 Clínic de Barcelona, 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 Clínic de Barcelona, 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 Clínic de Barcelona, 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 Clínic de Barcelona, 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, California, USA.,;
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35
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Wang X, Wang D, Zhang H, Feng M, Wu X. Genome-wide analysis of DNA methylation identifies two CpG sites for the early screening of colorectal cancer. Epigenomics 2020; 12:37-52. [PMID: 31762318 DOI: 10.2217/epi-2019-0299] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Aim: To identify a panel of DNA methylation markers for the early diagnosis of colorectal cancer (CRC). Materials & methods: Using public omics data and our pyrosequencing data, we developed and validated a global methylation model and a CpG-methylation-based model for CRC screening. Results: Both of the models yielded high sensitivity and specificity for distinguishing CRC and its precursors (colorectal adenoma and colorectal laterally spreading tumor) from normal controls in eight independent datasets and our newly collected samples. More importantly, the two-CpG-based model showed high specificity in excluding inflammatory bowel diseases and other 13 cancer types. Conclusion: A diagnostic model based on two CpGs (cg09239744 and cg12587766) may be a powerful tool for CRC screening.
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Affiliation(s)
- Xiaokang Wang
- Key Laboratory of Cancer Prevention & Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300000, PR China
| | - Danwen Wang
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Clinical Cancer Study Center of Hubei Province, Wuhan 430000, PR China
| | - Haoran Zhang
- Key Laboratory of Cancer Prevention & Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300000, PR China
| | - Maohui Feng
- Department of Gastrointestinal Surgery, Zhongnan Hospital of Wuhan University, Clinical Cancer Study Center of Hubei Province, Wuhan 430000, PR China
| | - Xiongzhi Wu
- Key Laboratory of Cancer Prevention & Therapy, Tianjin’s Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute & Hospital, Tianjin 300000, PR China
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36
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Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenetics 2019; 11:174. [PMID: 31791394 PMCID: PMC6888921 DOI: 10.1186/s13148-019-0776-0] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 11/05/2019] [Indexed: 12/14/2022] Open
Abstract
The flexibility of the epigenome has generated an enticing argument to explore its reversion through pharmacological treatments as a strategy to ameliorate disease phenotypes. All three families of epigenetic proteins—readers, writers, and erasers—are druggable targets that can be addressed through small-molecule inhibitors. At present, a few drugs targeting epigenetic enzymes as well as analogues of epigenetic modifications have been introduced into the clinic use (e.g. to treat haematological malignancies), and a wide range of epigenetic-based drugs are undergoing clinical trials. Here, we describe the timeline of epigenetic drug discovery and development beginning with the early design based solely on phenotypic observations to the state-of-the-art rational epigenetic drug discovery using validated targets. Finally, we will highlight some of the major aspects that need further research and discuss the challenges that need to be overcome to implement epigenetic drug discovery into clinical management of human disorders. To turn into reality, researchers from various disciplines (chemists, biologists, clinicians) need to work together to optimise the drug engineering, read-out assays, and clinical trial design.
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Affiliation(s)
- A Ganesan
- School of Pharmacy, University of East Anglia, Norwich, NR4 7TJ, UK
| | - Paola B Arimondo
- Epigenetic Chemical Biology, Institut Pasteur, CNRS UMR3523, 28 rue du Docteur Roux, 75724, Paris, France
| | - Marianne G Rots
- Epigenetic Editing, Dept. Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713, GZ, Groningen, The Netherlands
| | - Carmen Jeronimo
- Cancer Biology & Epigenetics Group, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal.,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - María Berdasco
- Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Biomedical Research Institute (IDIBELL), Barcelona, Catalonia, Spain. .,Epigenetic Therapies, Josep Carreras Leukaemia Research Institute (IJC), IJC Building, Campus ICO-Germans Trias i Pujol, Ctra de Can Ruti, Camí de les Escoles s/n 08916 Badalona, Barcelona, Catalonia, Spain.
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Locke WJ, Guanzon D, Ma C, Liew YJ, Duesing KR, Fung KYC, Ross JP. DNA Methylation Cancer Biomarkers: Translation to the Clinic. Front Genet 2019; 10:1150. [PMID: 31803237 PMCID: PMC6870840 DOI: 10.3389/fgene.2019.01150] [Citation(s) in RCA: 284] [Impact Index Per Article: 47.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 10/22/2019] [Indexed: 12/23/2022] Open
Abstract
Carcinogenesis is accompanied by widespread DNA methylation changes within the cell. These changes are characterized by a globally hypomethylated genome with focal hypermethylation of numerous 5’-cytosine-phosphate-guanine-3’ (CpG) islands, often spanning gene promoters and first exons. Many of these epigenetic changes occur early in tumorigenesis and are highly pervasive across a tumor type. This allows DNA methylation cancer biomarkers to be suitable for early detection and also to have utility across a range of areas relevant to cancer detection and treatment. Such tests are also simple in construction, as only one or a few loci need to be targeted for good test coverage. These properties make cancer-associated DNA methylation changes very attractive for development of cancer biomarker tests with substantive clinical utility. Across the patient journey from initial detection, to treatment and then monitoring, there are several points where DNA methylation assays can inform clinical practice. Assays on surgically removed tumor tissue are useful to determine indicators of treatment resistance, prognostication of outcome, or to molecularly characterize, classify, and determine the tissue of origin of a tumor. Cancer-associated DNA methylation changes can also be detected with accuracy in the cell-free DNA present in blood, stool, urine, and other biosamples. Such tests hold great promise for the development of simple, economical, and highly specific cancer detection tests suitable for population-wide screening, with several successfully translated examples already. The ability of circulating tumor DNA liquid biopsy assays to monitor cancer in situ also allows for the ability to monitor response to therapy, to detect minimal residual disease and as an early biomarker for cancer recurrence. This review will summarize existing DNA methylation cancer biomarkers used in clinical practice across the application domains above, discuss what makes a suitable DNA methylation cancer biomarker, and identify barriers to translation. We discuss technical factors such as the analytical performance and product-market fit, factors that contribute to successful downstream investment, including geography, and how this impacts intellectual property, regulatory hurdles, and the future of the marketplace and healthcare system.
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Affiliation(s)
- Warwick J Locke
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia.,Probing Biosystems Future Science Platform, CSIRO Health and Biosecurity, Canberra, ACT, Australia
| | - Dominic Guanzon
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia.,Probing Biosystems Future Science Platform, CSIRO Health and Biosecurity, Canberra, ACT, Australia
| | - Chenkai Ma
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia
| | - Yi Jin Liew
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia.,Probing Biosystems Future Science Platform, CSIRO Health and Biosecurity, Canberra, ACT, Australia
| | - Konsta R Duesing
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia
| | - Kim Y C Fung
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia.,Probing Biosystems Future Science Platform, CSIRO Health and Biosecurity, Canberra, ACT, Australia
| | - Jason P Ross
- Molecular Diagnostics Solutions, CSIRO Health and Biosecurity, North Ryde, NSW, Australia.,Probing Biosystems Future Science Platform, CSIRO Health and Biosecurity, Canberra, ACT, Australia
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38
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Lu JJ, Yuan Z. Application of DNA methylation in early diagnosis and treatment of pancreatic cancer. Shijie Huaren Xiaohua Zazhi 2019; 27:13-19. [DOI: 10.11569/wcjd.v27.i1.13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most malignant gastrointestinal tumors, characterized by a poor prognosis. Most of the patients have an advanced disease at the time of diagnosis and lose the opportunity of radical surgery, resulting in a 5-year survival rate of less than 5%. Circulating tumor DNA, whose concentration in plasma of patients with pancreatic adenocarcinoma is higher than that in health controls, carries specific gene mutation and aberrant DNA methylation. Epigenetic change is one of the important characteristics of cell carcinogenesis. DNA methylation is an early event in tumorigenesis, which is more helpful for early diagnosis than gene mutation and can be observed in each stage of PC. Therefore, the detection of aberrant DNA methylation in the promoter region in patients with PC may be a non-invasive method for early cancer detection, predicting prognosis, and monitoring recurrence. In the present review, we discuss the recent advances in the study of DNA methylation in the early diagnosis of PC, and the potential application value in the treatment of PC.
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Affiliation(s)
- Jia-Jun Lu
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zhou Yuan
- Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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39
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Chauvin A, Boisvert FM. Clinical Proteomics in Colorectal Cancer, a Promising Tool for Improving Personalised Medicine. Proteomes 2018; 6:proteomes6040049. [PMID: 30513835 PMCID: PMC6313903 DOI: 10.3390/proteomes6040049] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/22/2018] [Accepted: 11/29/2018] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer is the third most common and the fourth most lethal cancer worldwide. In most of cases, patients are diagnosed at an advanced or even metastatic stage, thus explaining the high mortality. The lack of proper clinical tests and the complicated procedures currently used for detecting this cancer, as well as for predicting the response to treatment and the outcome of a patient's resistance in guiding clinical practice, are key elements driving the search for biomarkers. In the present overview, the different biomarkers (diagnostic, prognostic, treatment resistance) discovered through proteomics studies in various colorectal cancer study models (blood, stool, biopsies), including the different proteomic techniques used for the discovery of these biomarkers, are reviewed, as well as the various tests used in clinical practice and those currently in clinical phase. These studies define the limits and perspectives related to proteomic biomarker research for personalised medicine in colorectal cancer.
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Affiliation(s)
- Anaïs Chauvin
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
| | - François-Michel Boisvert
- Department of Anatomy and Cell Biology, Université de Sherbrooke, 3201 Jean-Mignault, Sherbrooke, QC J1E 4K8, Canada.
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40
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Vedeld HM, Goel A, Lind GE. Epigenetic biomarkers in gastrointestinal cancers: The current state and clinical perspectives. Semin Cancer Biol 2018; 51:36-49. [PMID: 29253542 PMCID: PMC7286571 DOI: 10.1016/j.semcancer.2017.12.004] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 11/17/2017] [Accepted: 12/12/2017] [Indexed: 02/07/2023]
Abstract
Each year, almost 4.1 million people are diagnosed with gastrointestinal (GI) cancers. Due to late detection of this disease, the mortality is high, causing approximately 3 million cancer-related deaths annually, worldwide. Although the incidence and survival differs according to organ site, earlier detection and improved prognostication have the potential to reduce overall mortality burden from these cancers. Epigenetic changes, including aberrant promoter DNA methylation, are common events in both cancer initiation and progression. Furthermore, such changes may be identified non-invasively with the use of PCR based methods, in bodily fluids of cancer patients. These features make aberrant DNA methylation a promising substrate for the development of disease biomarkers for early detection, prognosis and for predicting response to therapy. In this article, we will provide an update and current clinical perspectives for DNA methylation alterations in patients with colorectal, gastric, pancreatic, liver and esophageal cancers, and discuss their potential role as cancer biomarkers.
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Affiliation(s)
- Hege Marie Vedeld
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Ajay Goel
- Center for Gastrointestinal Research, and Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway; K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
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41
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Lee PY, Chin SF, Low TY, Jamal R. Probing the colorectal cancer proteome for biomarkers: Current status and perspectives. J Proteomics 2018; 187:93-105. [PMID: 29953962 DOI: 10.1016/j.jprot.2018.06.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 06/13/2018] [Accepted: 06/23/2018] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignancies worldwide. Biomarkers that can facilitate better clinical management of CRC are in high demand to improve patient outcome and to reduce mortality. In this regard, proteomic analysis holds a promising prospect in the hunt of novel biomarkers for CRC and in understanding the mechanisms underlying tumorigenesis. This review aims to provide an overview of the current progress of proteomic research, focusing on discovery and validation of diagnostic biomarkers for CRC. We will summarize the contributions of proteomic strategies to recent discoveries of protein biomarkers for CRC and also briefly discuss the potential and challenges of different proteomic approaches in biomarker discovery and translational applications.
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Affiliation(s)
- Pey Yee Lee
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia.
| | - Siok-Fong Chin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
| | - Rahman Jamal
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, 56000 Kuala Lumpur, Malaysia
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Wong CC, Li W, Chan B, Yu J. Epigenomic biomarkers for prognostication and diagnosis of gastrointestinal cancers. Semin Cancer Biol 2018; 55:90-105. [PMID: 29665409 DOI: 10.1016/j.semcancer.2018.04.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Revised: 04/04/2018] [Accepted: 04/10/2018] [Indexed: 12/12/2022]
Abstract
Altered epigenetic regulation is central to many human diseases, including cancer. Over the past two decade, major advances have been made in our understanding of the role of epigenetic alterations in carcinogenesis, particularly for DNA methylation, histone modifications and non-coding RNAs. Aberrant hypermethylation of DNA at CpG islands is a well-established phenomenon that mediates transcriptional silencing of tumor suppressor genes, and it is an early event integral to gastrointestinal cancer development. As such, detection of aberrant DNA methylation is being developed as biomarkers for prognostic and diagnostic purposes in gastrointestinal cancers. Diverse tissue types are suitable for the analyses of methylated DNA, such as tumor tissues, blood, plasma, and stool, and some of these markers are already utilized in the clinical setting. Recent advances in the genome-wide epigenomic approaches are enabling the comprehensive mapping of the cancer methylome, thus providing new avenues for mining novel biomarkers for disease prognosis and diagnosis. Here, we review the current knowledge on DNA methylation biomarkers for the prognostication and non-invasive diagnosis of gastrointestinal cancers and highlight their clinical application.
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Affiliation(s)
- Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
| | - Weilin Li
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong; Department of Surgery, The Chinese University of Hong Kong, Hong Kong
| | - Bertina Chan
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, The Chinese University of Hong Kong, Hong Kong.
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Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum. Cancers (Basel) 2018; 10:cancers10040101. [PMID: 29614786 PMCID: PMC5923356 DOI: 10.3390/cancers10040101] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Revised: 03/23/2018] [Accepted: 03/27/2018] [Indexed: 02/06/2023] Open
Abstract
Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis—these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum.
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Freitas M, Ferreira F, Carvalho S, Silva F, Lopes P, Antunes L, Salta S, Diniz F, Santos LL, Videira JF, Henrique R, Jerónimo C. A novel DNA methylation panel accurately detects colorectal cancer independently of molecular pathway. J Transl Med 2018; 16:45. [PMID: 29486770 PMCID: PMC6389195 DOI: 10.1186/s12967-018-1415-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Accepted: 02/16/2018] [Indexed: 12/14/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the most incident cancers, associated with significant morbidity and mortality, and usually classified into three main molecular pathways: chromosomal instability, microsatellite instability (MSI) and CpG island methylator phenotype (CIMP). Currently, available screening methods are either costly or of limited specificity, impairing global implementation. More cost-effective strategies, including DNA methylation-based tests, might prove advantageous. Although some are already available, its performance is suboptimal, entailing the need for better candidate biomarkers. Herein, we tested whether combined use of APC, IGF2, MGMT, RASSF1A, and SEPT9 promoter methylation might accurately detect CRC irrespective of molecular subtype. Methods Selected genes were validated using formalin-fixed paraffin-embedded tissues from 214 CRC and 50 non-malignant colorectal mucosae (CRN). Promoter methylation levels were assessed using real-time quantitative methylation-specific PCR. MSI and CIMP status were determined. Molecular data were correlated with standard clinicopathological features. Diagnostic and prognostic performances were evaluated by receiver operator characteristics curve and survival analyses, respectively. Results Except for IGF2, promoter methylation levels were significantly higher in CRC compared to CRN. A three-gene panel (MGMT, RASSF1A, SEPT9) identified malignancy with 96.6% sensitivity, 74.0% specificity and 91.5 positive predictive value (area under the curve: 0.97), independently of tumor location, stage, and molecular pathway. Conclusions Combined promoter methylation analysis of MGMT/RASSF1A/SEPT9 displays a better performance than currently available epigenetic-based biomarkers for CRC, providing the basis for the development of a non-invasive assay to detect CRC irrespective of the molecular pathway. Electronic supplementary material The online version of this article (10.1186/s12967-018-1415-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Micaela Freitas
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Fábio Ferreira
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Sónia Carvalho
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Fernanda Silva
- Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Paula Lopes
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal.,Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Luís Antunes
- Departments of Epidemiology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Sofia Salta
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Francisca Diniz
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal
| | - Lúcio Lara Santos
- Departments of Surgical Oncology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - José Flávio Videira
- Departments of Surgical Oncology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal
| | - Rui Henrique
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Departments of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal. .,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313, Porto, Portugal.
| | - Carmen Jerónimo
- Cancer Biology & Epigenetics Group-Research Center (CI-IPOP), Research Center-LAB 3, Portuguese Oncology Institute of Porto (IPO Porto), F Bdg, 1st Floor, Rua Dr António Bernardino de Almeida, 4200-072, Porto, Portugal. .,Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua de Jorge Viterbo Ferreira n.º 228, 4050-313, Porto, Portugal.
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El Bairi K, Tariq K, Himri I, Jaafari A, Smaili W, Kandhro AH, Gouri A, Ghazi B. Decoding colorectal cancer epigenomics. Cancer Genet 2018; 220:49-76. [PMID: 29310839 DOI: 10.1016/j.cancergen.2017.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 11/01/2017] [Accepted: 11/06/2017] [Indexed: 02/07/2023]
Abstract
Colorectal cancer (CRC) is very heterogeneous and presents different types of epigenetic alterations including DNA methylation, histone modifications and microRNAs. These changes are considered as characteristics of various observed clinical phenotypes. Undoubtedly, the discovery of epigenetic pathways with novel epigenetic-related mechanisms constitutes a promising advance in cancer biomarker discovery. In this review, we provide an evidence-based discussing of the current understanding of CRC epigenomics and its role in initiation, epithelial-to-mesenchymal transition and metastasis. We also discuss the recent findings regarding the potential clinical perspectives of these alterations as potent biomarkers for CRC diagnosis, prognosis, and therapy in the era of liquid biopsy.
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Affiliation(s)
- Khalid El Bairi
- Independent Research Team in Cancer Biology and Bioactive Compounds, Mohamed 1(st) University, Oujda, Morocco.
| | - Kanwal Tariq
- B-10 Jumani Center, Garden East, Karachi 74400, Pakistan
| | - Imane Himri
- Laboratory of Biochemistry, Faculty of Sciences, Mohamed I(st) Universiy, Oujda, Morocco; Delegation of the Ministry of Health, Oujda, Morocco
| | - Abdeslam Jaafari
- Laboratoire de Génie Biologique, Equipe d'Immunopharmacologie, Faculté des Sciences et Techniques, Université Sultan Moulay Slimane, Beni Mellal, Maroc
| | - Wiam Smaili
- Centre de Génomique Humaine, Faculté de Médecine et de Pharmacie, Université Mohamed V, Rabat, Maroc; Département de Génétique Médicale, Institut National d'Hygiène, Rabat, Maroc
| | - Abdul Hafeez Kandhro
- Department of Biochemistry, Healthcare Molecular and Diagnostic Laboratory, Hyderabad, Pakistan
| | - Adel Gouri
- Laboratory of Medical Biochemistry, Ibn Rochd University Hospital, Annaba, Algeria
| | - Bouchra Ghazi
- National Laboratory of Reference, Faculty of Medicine, Mohammed VI University of Health Sciences (UM6SS), Casablanca, Morocco
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46
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Puccini A, Berger MD, Naseem M, Tokunaga R, Battaglin F, Cao S, Hanna DL, McSkane M, Soni S, Zhang W, Lenz HJ. Colorectal cancer: epigenetic alterations and their clinical implications. Biochim Biophys Acta Rev Cancer 2017; 1868:439-448. [PMID: 28939182 DOI: 10.1016/j.bbcan.2017.09.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Revised: 09/16/2017] [Accepted: 09/17/2017] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with distinct molecular and clinical features, which reflects the wide range of prognostic outcomes and treatment responses observed among CRC patients worldwide. Our understanding of the CRC epigenome has been largely developed over the last decade and it is now believed that among thousands of epigenetic alterations present in each tumor, a small subgroup of these may be considered as a CRC driver event. DNA methylation profiles have been the most widely studied in CRC, which includes a subset of patients with distinct molecular and clinical features now categorized as CpG island methylator phenotype (CIMP). Major advances have been made in our capacity to detect epigenetic alterations, providing us with new potential biomarkers for diagnostic, prognostic and therapeutic purposes. This review aims to summarize our current knowledge about epigenetic alterations occurring in CRC, underlying their potential future clinical implications in terms of diagnosis, prognosis and therapeutic strategies for CRC patients.
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Affiliation(s)
- Alberto Puccini
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Martin D Berger
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Madiha Naseem
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Ryuma Tokunaga
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Diana L Hanna
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Michelle McSkane
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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47
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Singh MP, Rai S, Suyal S, Singh SK, Singh NK, Agarwal A, Srivastava S. Genetic and epigenetic markers in colorectal cancer screening: recent advances. Expert Rev Mol Diagn 2017; 17:665-685. [PMID: 28562109 DOI: 10.1080/14737159.2017.1337511] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is a heterogenous disease which develops from benign intraepithelial lesions known as adenomas to malignant carcinomas. Acquired alterations in Wnt signaling, TGFβ, MAPK pathway genes and clonal propagation of altered cells are responsible for this transformation. Detection of adenomas or early stage cancer in asymptomatic patients and better prognostic and predictive markers is important for improving the clinical management of CRC. Area covered: In this review, the authors have evaluated the potential of genetic and epigenetic alterations as markers for early detection, prognosis and therapeutic predictive potential in the context of CRC. We have discussed molecular heterogeneity present in CRC and its correlation to prognosis and response to therapy. Expert commentary: Molecular marker based CRC screening methods still fail to gain trust of clinicians. Invasive screening methods, molecular heterogeneity, chemoresistance and low quality test samples are some key challenges which need to be addressed in the present context. New sequencing technologies and integrated omics data analysis of individual or population cohort results in GWAS. MPE studies following a GWAS could be future line of research to establish accurate correlations between CRC and its risk factors. This strategy would identify most reliable biomarkers for CRC screening and management.
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Affiliation(s)
- Manish Pratap Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Sandhya Rai
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Shradha Suyal
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Sunil Kumar Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Nand Kumar Singh
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
| | - Akash Agarwal
- b Department of Surgical Oncology , Dr. Ram Manohar Lohia Institute of Medical Sciences (DRMLIMS) , Lucknow , India
| | - Sameer Srivastava
- a Department of Biotechnology , Motilal Nehru National Institute of Technology (MNNIT) Allahabad , India
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Ning W, Li H, Meng F, Cheng J, Song X, Zhang G, Wang W, Wu S, Fang J, Ma K, Yang J, Pei D, Dong F. Identification of differential metabolic characteristics between tumor and normal tissue from colorectal cancer patients by gas chromatography-mass spectrometry. Biomed Chromatogr 2017; 31. [PMID: 28475217 DOI: 10.1002/bmc.3999] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/25/2017] [Accepted: 05/02/2017] [Indexed: 12/14/2022]
Abstract
Colorectal cancer (CRC) is one of the most common human malignancies and encompasses cancers of the colon and rectum. Although the gold-standard colonoscopy screening method is effective in detecting CRC, this method is invasive and can result in severe complications for patients. The purpose of this study was to determine differences in metabolites between CRC and matched adjacent nontumor tissues from CRC patients, to identify potential biomarkers that may be informative and developed screening methods. Metabolomic analysis was performed on clinically localized CRC tissue and matched adjacent nontumor tissue from 20 CRC patients. Unsupervised analysis, supervised analysis, univariate analysis and pathway analysis were used to identify potential metabolic biomarkers of CRC. The levels of 25 metabolites in CRC tissues were significantly altered compared with the matched adjacent nontumor tissues. Four metabolites (lactic acid, alanine, phosphate and aspartic acid) demonstrated good area under the curve of receiver-operator characteristic with acceptable sensitivities and specificities, indicating their potential as important biomarkers for CRC. Alterations of amino acid metabolism and enhanced glycolysis may be major factors in the development and progression of CRC. Lactic acid, alanine, phosphate, and aspartic acid could be effective diagnostic indicators for CRC.
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Affiliation(s)
- Wu Ning
- China-Japan Friendship Hospital, Beijing, China
| | - Haijing Li
- National Center of Biomedical Analysis, Beijing, China
| | | | - Jianhua Cheng
- National Center of Biomedical Analysis, Beijing, China
| | - Xin Song
- China-Japan Friendship Hospital, Beijing, China
| | | | - Wenyue Wang
- China-Japan Friendship Hospital, Beijing, China
| | - Shengming Wu
- National Center of Biomedical Analysis, Beijing, China
| | - Junjian Fang
- National Center of Biomedical Analysis, Beijing, China
| | - Kunpeng Ma
- National Center of Biomedical Analysis, Beijing, China
| | - Jie Yang
- National Center of Biomedical Analysis, Beijing, China
| | - Dongpo Pei
- China-Japan Friendship Hospital, Beijing, China
| | - Fangting Dong
- National Center of Biomedical Analysis, Beijing, China
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Kinehara M, Yamamoto Y, Shiroma Y, Ikuo M, Shimamoto A, Tahara H. DNA and Histone Modifications in Cancer Diagnosis. CANCER DRUG DISCOVERY AND DEVELOPMENT 2017:533-584. [DOI: 10.1007/978-3-319-59786-7_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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50
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Lam K, Pan K, Linnekamp JF, Medema JP, Kandimalla R. DNA methylation based biomarkers in colorectal cancer: A systematic review. Biochim Biophys Acta Rev Cancer 2016; 1866:106-20. [PMID: 27385266 DOI: 10.1016/j.bbcan.2016.07.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Revised: 06/30/2016] [Accepted: 07/01/2016] [Indexed: 12/11/2022]
Abstract
Since genetic and epigenetic alterations influence the development of colorectal cancer (CRC), huge potential lies in the use of DNA methylation as biomarkers to improve the current diagnosis, screening, prognosis and treatment prediction. Here we performed a systematic review on DNA methylation-based biomarkers published in CRC, and discussed the current state of findings and future challenges. Based on the findings, we then provide a perspective on future studies. Genome-wide studies on DNA methylation revealed novel biomarkers as well as distinct subgroups that exist in CRC. For diagnostic purposes, the most independently validated genes to study further are VIM, SEPT9, ITGA4, OSM4, GATA4 and NDRG4. These hypermethylated biomarkers can even be combined with LINE1 hypomethylation and the performance of markers should be examined in comparison to FIT further to find sensitive combinations. In terms of prognostic markers, myopodin, KISS1, TMEFF2, HLTF, hMLH1, APAF1, BCL2 and p53 are independently validated. Most prognostic markers published lack both a multivariate analysis in comparison to clinical risk factors and the appropriate patient group who will benefit by adjuvant chemotherapy. Methylation of IGFBP3, mir148a and PTEN are found to be predictive markers for 5-FU and EGFR therapy respectively. For therapy prediction, more studies should focus on finding markers for chemotherapeutic drugs as majority of the patients would benefit. Translation of these biomarkers into clinical utility would require large-scale prospective cohorts and randomized clinical trials in future. Based on these findings and consideration we propose an avenue to introduce methylation markers into clinical practice in near future. For future studies, multi-omics profiling on matched tissue and non-invasive cohorts along with matched cohorts of adenoma to carcinoma is indispensable to concurrently stratify CRC and find novel, robust biomarkers. Moreover, future studies should examine the timing and heterogeneity of methylation as well as the difference in methylation levels between epithelial and stromal tissues.
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Affiliation(s)
- Kevin Lam
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Kathy Pan
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Janneke Fiona Linnekamp
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Jan Paul Medema
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands
| | - Raju Kandimalla
- Laboratory for Experimental Oncology and Radiobiology (LEXOR), Center for Experimental Molecular Medicine (CEMM), Academic Medical Center (AMC), University of Amsterdam, Amsterdam, The Netherlands.
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