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Stojchevski R, Sutanto EA, Sutanto R, Hadzi-Petrushev N, Mladenov M, Singh SR, Sinha JK, Ghosh S, Yarlagadda B, Singh KK, Verma P, Sengupta S, Bhaskar R, Avtanski D. Translational Advances in Oncogene and Tumor-Suppressor Gene Research. Cancers (Basel) 2025; 17:1008. [PMID: 40149342 PMCID: PMC11940485 DOI: 10.3390/cancers17061008] [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: 02/10/2025] [Revised: 03/10/2025] [Accepted: 03/15/2025] [Indexed: 03/29/2025] Open
Abstract
Cancer, characterized by the uncontrolled proliferation of cells, is one of the leading causes of death globally, with approximately one in five people developing the disease in their lifetime. While many driver genes were identified decades ago, and most cancers can be classified based on morphology and progression, there is still a significant gap in knowledge about genetic aberrations and nuclear DNA damage. The study of two critical groups of genes-tumor suppressors, which inhibit proliferation and promote apoptosis, and oncogenes, which regulate proliferation and survival-can help to understand the genomic causes behind tumorigenesis, leading to more personalized approaches to diagnosis and treatment. Aberration of tumor suppressors, which undergo two-hit and loss-of-function mutations, and oncogenes, activated forms of proto-oncogenes that experience one-hit and gain-of-function mutations, are responsible for the dysregulation of key signaling pathways that regulate cell division, such as p53, Rb, Ras/Raf/ERK/MAPK, PI3K/AKT, and Wnt/β-catenin. Modern breakthroughs in genomics research, like next-generation sequencing, have provided efficient strategies for mapping unique genomic changes that contribute to tumor heterogeneity. Novel therapeutic approaches have enabled personalized medicine, helping address genetic variability in tumor suppressors and oncogenes. This comprehensive review examines the molecular mechanisms behind tumor-suppressor genes and oncogenes, the key signaling pathways they regulate, epigenetic modifications, tumor heterogeneity, and the drug resistance mechanisms that drive carcinogenesis. Moreover, the review explores the clinical application of sequencing techniques, multiomics, diagnostic procedures, pharmacogenomics, and personalized treatment and prevention options, discussing future directions for emerging technologies.
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Affiliation(s)
- Radoslav Stojchevski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
| | - Edward Agus Sutanto
- CUNY School of Medicine, The City College of New York, 160 Convent Avenue, New York, NY 10031, USA;
| | - Rinni Sutanto
- New York Institute of Technology College of Osteopathic Medicine, Glen Head, NY 11545, USA;
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, Ss. Cyril and Methodius University, 1000 Skopje, North Macedonia; (N.H.-P.)
| | - Sajal Raj Singh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Jitendra Kumar Sinha
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | - Shampa Ghosh
- GloNeuro, Sector 107, Vishwakarma Road, Noida 201301, Uttar Pradesh, India (J.K.S.)
| | | | - Krishna Kumar Singh
- Symbiosis Centre for Information Technology (SCIT), Rajiv Gandhi InfoTech Park, Hinjawadi, Pune 411057, Maharashtra, India;
| | - Prashant Verma
- School of Management, BML Munjal University, NH8, Sidhrawali, Gurugram 122413, Haryana, India
| | - Sonali Sengupta
- Department of Gastroenterology, All India Institute of Medical Sciences (AIIMS), New Delhi 110029, India
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan 38541, Republic of Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Republic of Korea
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, New York, NY 10022, USA;
- Feinstein Institutes for Medical Research, Manhasset, NY 11030, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY 11549, USA
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Jardanowska-Kotuniak M, Dramiński M, Własnowolski M, Łapiński M, Sengupta K, Agarwal A, Filip A, Ghosh N, Pancaldi V, Grynberg M, Saha I, Plewczynski D, Dąbrowski MJ. Unveiling epigenetic regulatory elements associated with breast cancer development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.11.12.623187. [PMID: 39605637 PMCID: PMC11601335 DOI: 10.1101/2024.11.12.623187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
Breast cancer is the most common cancer in women and the 2nd most common cancer worldwide, yearly impacting over 2 million females and causing 650 thousand deaths. It has been widely studied, but its epigenetic variation is not entirely unveiled. We aimed to identify epigenetic mechanisms impacting the expression of breast cancer related genes to detect new potential biomarkers and therapeutic targets. We considered The Cancer Genome Atlas database with over 800 samples and several omics datasets such as mRNA, miRNA, DNA methylation, which we used to select 2701 features that were statistically significant to differ between cancer and control samples using the Monte Carlo Feature Selection and Interdependency Discovery algorithm, from an initial total of 417,486. Their biological impact on cancerogenesis was confirmed using: statistical analysis, natural language processing, linear and machine learning models as well as: transcription factors identification, drugs and 3D chromatin structure analyses. Classification of cancer vs control samples on the selected features returned high classification weighted Accuracy from 0.91 to 0.98 depending on feature-type: mRNA, miRNA, DNA methylation, and classification algorithm. In general, cancer samples showed lower expression of differentially expressed genes and increased β-values of differentially methylated sites. We identified mRNAs whose expression is well explained by miRNA expression and differentially methylated sites β-values. We recognized differentially methylated sites possibly affecting NRF1 and MXI1 transcription factors binding, causing a disturbance in NKAPL and PITX1 expression, respectively. Our 3D models showed more loosely packed chromatin in cancer. This study successfully points out numerous possible regulatory dependencies.
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Affiliation(s)
- Marta Jardanowska-Kotuniak
- Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland
- Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, Poland
| | - Michał Dramiński
- Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland
| | - Michał Własnowolski
- Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
| | - Marcin Łapiński
- Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland
| | - Kaustav Sengupta
- Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
| | - Abhishek Agarwal
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Adam Filip
- Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland
| | - Nimisha Ghosh
- Department of Computer Science and Information Technology, Institute of Technical Education and Research, Siksha O Anusandhan University, Bhubaneswar, Odisha, 751030, India
| | - Vera Pancaldi
- CRCT, Université de Toulouse, Inserm, CNRS, Université Toulouse III-Paul Sabatier, Centre de Recherches en Cancérologie de Toulouse, Toulouse, France
| | - Marcin Grynberg
- Institute of Biochemistry and Biophysics of the Polish Academy of Sciences, Warsaw, Poland
| | - Indrajit Saha
- Department of Computer Science and Engineering, National Institute of Technical Teachers’ Training and Research, Kolkata 700106, India
| | - Dariusz Plewczynski
- Laboratory of Bioinformatics and Computational Genomics, Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw, Poland
- Laboratory of Functional and Structural Genomics, Centre of New Technologies, University of Warsaw, Warsaw, Poland
| | - Michał J. Dąbrowski
- Computational Biology Group, Institute of Computer Science of the Polish Academy of Sciences, Warsaw, Poland
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Giovino C, Subasri V, Telfer F, Malkin D. New Paradigms in the Clinical Management of Li-Fraumeni Syndrome. Cold Spring Harb Perspect Med 2024; 14:a041584. [PMID: 38692744 PMCID: PMC11529854 DOI: 10.1101/cshperspect.a041584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/03/2024]
Abstract
Approximately 8.5%-16.2% of childhood cancers are associated with a pathogenic/likely pathogenic germline variant-a prevalence that is likely to rise with improvements in phenotype recognition, sequencing, and variant validation. One highly informative, classical hereditary cancer predisposition syndrome is Li-Fraumeni syndrome (LFS), associated with germline variants in the TP53 tumor suppressor gene, and a >90% cumulative lifetime cancer risk. In seeking to improve outcomes for young LFS patients, we must improve the specificity and sensitivity of existing cancer surveillance programs and explore how to complement early detection strategies with pharmacology-based risk-reduction interventions. Here, we describe novel precision screening technologies and clinical strategies for cancer risk reduction. In particular, we summarize the biomarkers for early diagnosis and risk stratification of LFS patients from birth, noninvasive and machine learning-based cancer screening, and drugs that have shown the potential to be repurposed for cancer prevention.
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Affiliation(s)
- Camilla Giovino
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Vallijah Subasri
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - Frank Telfer
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
| | - David Malkin
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 1L7, Canada
- Department of Medical Biophysics, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5G 1L7, Canada
- Institute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada
- Division of Hematology-Oncology, The Hospital for Sick Children, Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada
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Wang F, Zhao D, Xu WY, Liu Y, Sun H, Lu S, Ji Y, Jiang J, Chen Y, He Q, Gong C, Liu R, Su Z, Dong Y, Yan Z, Liu L. Blood leukocytes as a non-invasive diagnostic tool for thyroid nodules: a prospective cohort study. BMC Med 2024; 22:147. [PMID: 38561764 PMCID: PMC10986011 DOI: 10.1186/s12916-024-03368-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 03/22/2024] [Indexed: 04/04/2024] Open
Abstract
BACKGROUND Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy. METHODS This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes. RESULTS The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies. CONCLUSIONS This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.
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Affiliation(s)
- Feihang Wang
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Danyang Zhao
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Wang-Yang Xu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Yiying Liu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Huiyi Sun
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Shanshan Lu
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jingjing Jiang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Yi Chen
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China
| | - Qiye He
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | | | - Rui Liu
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China
| | - Zhixi Su
- Singlera Genomics (Shanghai) Ltd., Shanghai, 201203, China.
| | - Yi Dong
- Department of Ultrasound, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China.
| | - Zhiping Yan
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China.
| | - Lingxiao Liu
- Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- National Clinical Research Center for Interventional Medicine, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Medical Imaging, Shanghai, 200032, China.
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Wogu AF, Li H, Zhao S, Nichols HB, Cai J. Additive subdistribution hazards regression for competing risks data in case-cohort studies. Biometrics 2023; 79:3010-3022. [PMID: 36606409 PMCID: PMC10676749 DOI: 10.1111/biom.13821] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 12/20/2022] [Indexed: 01/07/2023]
Abstract
In survival data analysis, a competing risk is an event whose occurrence precludes or alters the chance of the occurrence of the primary event of interest. In large cohort studies with long-term follow-up, there are often competing risks. Further, if the event of interest is rare in such large studies, the case-cohort study design is widely used to reduce the cost and achieve the same efficiency as a cohort study. The conventional additive hazards modeling for competing risks data in case-cohort studies involves the cause-specific hazard function, under which direct assessment of covariate effects on the cumulative incidence function, or the subdistribution, is not possible. In this paper, we consider an additive hazard model for the subdistribution of a competing risk in case-cohort studies. We propose estimating equations based on inverse probability weighting methods for the estimation of the model parameters. Consistency and asymptotic normality of the proposed estimators are established. The performance of the proposed methods in finite samples is examined through simulation studies and the proposed approach is applied to a case-cohort dataset from the Sister Study.
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Affiliation(s)
- Adane F. Wogu
- Department of Biostatistics & Informatics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Haolin Li
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Shanshan Zhao
- Biostatistics & Computational Biology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA
| | - Hazel B. Nichols
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
| | - Jianwen Cai
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
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Sindi S, Hamdi N, Hassan S, Ganash M, Alharbi M, Alburae N, Azhari S, Alkhayyat S, Linjawi A, Alkhatabi H, Elaimi A, Alrefaei G, Alsubhi N, Alrafiah A, Alhazmi S. Promoter Methylation-Regulated Differentially Expressed Genes in Breast Cancer. BREAST CANCER (DOVE MEDICAL PRESS) 2023; 15:435-450. [PMID: 37434588 PMCID: PMC10332364 DOI: 10.2147/bctt.s408711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/21/2023] [Indexed: 07/13/2023]
Abstract
Background Breast cancer is one of the most common malignancies among women. Recent studies revealed that differentially methylated regions (DMRs) are implicated in regulating gene expression. The goal of this research was to determine which genes and pathways are dysregulated in breast cancer when their promoters are methylated in an abnormal way, leading to differential expression. Whole-genome bisulfite sequencing was applied to analyze DMRs for eight peripheral blood samples collected from five Saudi females diagnosed with stages I and II of breast cancer aligned with three normal females. Three of those patients and three normal samples were used to determine differentially expressed genes (DEG) using Illumina platform NovaSeq PE150. Results Based on ontology (GO) and KEGG pathways, the analysis indicated that DMGs and DEG are closely related to associated processes, such as ubiquitin-protein transferase activity, ubiquitin-mediated proteolysis, and oxidative phosphorylation. The findings indicated a potentially significant association between global hypomethylation and breast cancer in Saudi patients. Our results revealed 81 differentially promoter-methylated and expressed genes. The most significant differentially methylated and expressed genes found in gene ontology (GO) are pumilio RNA binding family member 1 (PUM1) and zinc finger AN1-type containing 2B (ZFAND2B) also known as (AIRAPL). Conclusion The essential outcomes of this study suggested that aberrant hypermethylation at crucial genes that have significant parts in the molecular pathways of breast cancer could be used as a potential prognostic biomarker for breast cancer.
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Affiliation(s)
- Samar Sindi
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Norah Hamdi
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Biology, King Khalid University, Abha, Saudi Arabia
| | - Sabah Hassan
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Magdah Ganash
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mona Alharbi
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Najla Alburae
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Sheren Azhari
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shadi Alkhayyat
- Department of Internal Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | | | - Heba Alkhatabi
- Hematology Research Unit (HRU), King Fahad Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Aisha Elaimi
- Department of Medical Laboratory Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Ghadeer Alrefaei
- Department of Biology, University of Jeddah, Jeddah, Saudi Arabia
| | - Nouf Alsubhi
- Biological Sciences Department, College of Science & Arts, King Abdulaziz University, Rabigh, Saudi Arabia
| | - Aziza Alrafiah
- Department of Medical Laboratory Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Safiah Alhazmi
- Department of Biological Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
- Princess Dr. Najla Bint Saud Al-Saud Center for Excellence Research in Biotechnology, King Abdulaziz University, Jeddah, Saudi Arabia
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Siri G, Mosallaei M, Ehtesham N, Rahimi H, Mazarei M, Nasrollahzadeh Sabet M, Behroozi J. TUSC3 Methylation in Peripheral Blood Cells as a Biomarker for Diagnosis of Colorectal Cancer. Adv Biomed Res 2023; 12:174. [PMID: 37564442 PMCID: PMC10410437 DOI: 10.4103/abr.abr_396_22] [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: 11/20/2022] [Revised: 02/14/2023] [Accepted: 02/21/2023] [Indexed: 08/12/2023] Open
Abstract
Background Several case-control studies have suggested that global and loci-specific deoxyribonucleic acid (DNA) methylation in peripheral blood mononuclear cells (PBMCs) of DNA might be potential biomarkers of cancer diagnosis and prognosis. In this study, for the first time, we intended to assess the diagnostic power of the methylation level of tumor suppressor candidate 3 (TUSC3) gene promoter in patients with colorectal cancer (CRC). Materials and Methods In the current study, we quantitatively assessed the promoter methylation level of TUSC3 in PBMCs of 70 CRC cases and 75 non-cancerous subjects via methylation quantification of endonuclease-resistant DNA (MethyQESD) method. Results The methylation level of the TUSC3 was meaningfully higher in CRC cases than in non-CRC subjects (43.55 ± 21.80% vs. 16.07 ± 13.63%, respectively; P < 0.001). The sensitivity and specificity of this gene for the detection of CRC were 88.6% and 76.0%, respectively. The receiver operating characteristic (ROC) curve examination discovered an area under the curve (AUC) of 0.880, representing a very high accuracy of the TUSC3 methylation marker in distinguishing CRC subjects from healthy individuals. However, there was no substantial diversity in methylation level between various CRC stages (P: 0.088). Conclusion For CRC screening, PBMCs are a reliable source for DNA methylation analysis and TUSC3 promoter methylation can be utilized as a hopeful biomarker for early and non-invasive diagnosis of CRC.
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Affiliation(s)
- Goli Siri
- Department of Internal Medicine, Amir-Alam Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Meysam Mosallaei
- Department of Genetics and Advanced Medical Technology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Naeim Ehtesham
- School of Medicine, Iranshahr University of Medical Sciences, Iranshahr, Iran
| | - Hasan Rahimi
- Faculty of Biostatistics, Tarbiat Modares University, Tehran, Iran
| | - Madineh Mazarei
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Science, Shahrekord, Iran
| | - Mehrdad Nasrollahzadeh Sabet
- Department of Genetics and Advanced Medical Technology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
| | - Javad Behroozi
- Department of Genetics and Advanced Medical Technology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
- Department of Genetics and Advanced Medical Technology, Faculty of Medicine, AJA University of Medical Sciences; Research Center for Cancer Screening and Epidemiology, AJA University of Medical Sciences, Tehran, Iran
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8
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Shankarappa B, Mahadevan J, Murthy P, Purushottam M, Viswanath B, Jain S, Devarbhavi H, Mysore Visweswariah A. Hypomethylation of Long Interspersed Nucleotide Elements and Aldehyde Dehydrogenase in Patients of Alcohol Use Disorder with Cirrhosis. DNA Cell Biol 2023. [PMID: 37367217 DOI: 10.1089/dna.2022.0669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023] Open
Abstract
Alcohol use disorder (AUD) and cirrhosis are key outcomes of excessive alcohol use, and a genetic influence in these outcomes is increasingly recognized. While 80-90% of heavy alcohol users show evidence of fatty liver, only 10-20% progress to cirrhosis. There is currently no clear understanding of the causes of this difference in progression. The aim of this study is to evaluate genetics and epigenetics at the aldehyde dehydrogenase (ALDH2) locus in patients with AUD and liver complications. Study participants were inpatients from the clinical services of Gastroenterology and Psychiatry at St. John's Medical College Hospital (SJMCH) and the National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. Men diagnosed as having AUD with cirrhosis (AUDC+ve, N = 136) and AUD without cirrhosis (AUDC-ve, N = 107) were assessed. FibroScan/sonographic evidence was used to rule out fibrosis in the AUDC-ve group. Genomic DNA was used for genotyping at the ALDH2 (rs2238151) locus. A subset of 89 samples was used for DNA methylation (AUDC+ve, N = 44; and AUDC-ve, N = 45) analysis at long interspersed nucleotide element 1 (LINE-1) and ALDH2 cytosine-phosphate-guanine (CpG) loci by pyrosequencing. ALDH2 DNA methylation was significantly lower in the AUDC+ve group compared with the AUDC-ve group (p < 0.001). Lower methylation was associated with a risk allele (T) of the ALDH2 locus (rs2238151) (p = 0.01). Global (LINE-1) DNA methylation levels were also significantly lower in the AUDC+ve group compared with the AUDC-ve group (p = 0.01). Compromised global methylation (LINE-1) and hypomethylation at the ALDH2 gene was observed in patients with cirrhosis compared with those without cirrhosis. DNA methylation could be explored as a biomarker for cirrhosis and liver complications.
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Affiliation(s)
- Bhagyalakshmi Shankarappa
- Department of Psychiatry, St. John's Medical College Hospital, Bangalore, India
- Molecular Genetics Laboratory, Department of Psychiatry, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Jayant Mahadevan
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Pratima Murthy
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Meera Purushottam
- Molecular Genetics Laboratory, Department of Psychiatry, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Biju Viswanath
- Molecular Genetics Laboratory, Department of Psychiatry, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Sanjeev Jain
- Molecular Genetics Laboratory, Department of Psychiatry, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
- Department of Psychiatry, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India
| | - Harshad Devarbhavi
- Department of Gastroenterology, St. John's Medical College Hospital, Bangalore, India
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Itoh H, Harada KH, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Yokoyama K, Zhu J, Harada Sassa M, Yoshida T, Tsugane S, Iwasaki M. Association between serum concentrations of perfluoroalkyl substances and global DNA methylation levels in peripheral blood leukocytes of Japanese women: A cross-sectional study. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 859:159923. [PMID: 36356761 DOI: 10.1016/j.scitotenv.2022.159923] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 10/05/2022] [Accepted: 10/30/2022] [Indexed: 06/16/2023]
Abstract
Global DNA methylation levels in peripheral blood leukocytes can be a biomarker for cancer risk; however, levels can be changed by various factors such as environmental pollutants. We investigated the association between serum concentrations of perfluoroalkyl substances (PFASs) and global DNA methylation levels of leukocytes in a cross-sectional study using the control group of a Japanese breast cancer case-control study [397 women with a mean age of 54.1 (SD 10.1) years]. Importantly, our analysis distinguished branched PFAS isomers as different from linear isomers. The serum concentrations of 20 PFASs were measured by in-port arylation gas-chromatography negative chemical ionization mass spectrometry. Global DNA methylation levels in peripheral blood leukocytes were measured using a luminometric methylation assay. Associations between log10-transformed serum PFAS concentrations and global DNA methylation levels were evaluated by regression coefficients in multivariable robust linear regression analyses. Serum concentrations of 13 PFASs were significantly associated with increased global DNA methylation levels in leukocytes. Global DNA methylation was significantly increased by 1.45 %-3.96 % per log10-unit increase of serum PFAS concentration. Our results indicate that exposure to PFASs may increase global DNA methylation levels in peripheral blood leukocytes of Japanese women.
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Affiliation(s)
- Hiroaki Itoh
- Department of Epidemiology and Environmental Health, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
| | - Kouji H Harada
- Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida, Kyoto 606-8501, Japan
| | - Yoshio Kasuga
- Department of Surgery, Nagano Matsushiro General Hospital, 183 Matsushiro, Matsushiro-cho, Nagano, Nagano 381-1231, Japan; Department of Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
| | - Shiro Yokoyama
- Department of Breast and Thyroid Surgery, Nagano Red Cross Hospital, 5-22-1 Wakasato, Nagano, Nagano 380-8582, Japan
| | - Hiroshi Onuma
- Department of Breast and Thyroid Surgery, Nagano Red Cross Hospital, 5-22-1 Wakasato, Nagano, Nagano 380-8582, Japan
| | - Hideki Nishimura
- Department of Chest Surgery and Breast Surgery, Nagano Municipal Hospital, 1333-1 Tomitake, Nagano, Nagano 381-8551, Japan
| | - Ritsu Kusama
- Department of Surgery, Hokushin General Hospital, 1-5-63 Nishi, Nakano, Nagano 383-8505, Japan
| | - Kazuhito Yokoyama
- Department of Epidemiology and Environmental Health, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan; Department of Epidemiology and Social Medicine, International University of Health and Welfare Graduate School of Public Health, 4-1-26 Akasaka, Minato-ku, Tokyo 107-8402, Japan
| | - Jing Zhu
- Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida, Kyoto 606-8501, Japan; Department of Sanitary Technology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610061, China
| | - Mariko Harada Sassa
- Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine, Yoshida, Kyoto 606-8501, Japan
| | - Teruhiko Yoshida
- Division of Genetics, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Shoichiro Tsugane
- Division of Cohort Research, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Motoki Iwasaki
- Division of Epidemiology, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; Division of Cohort Research, National Cancer Center Institute for Cancer Control, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
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10
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Hong X, Wu Z, Cao W, Lv J, Yu C, Huang T, Sun D, Liao C, Pang Y, Pang Z, Cong L, Wang H, Wu X, Liu Y, Gao W, Li L. Longitudinal Association of DNA Methylation With Type 2 Diabetes and Glycemic Traits: A 5-Year Cross-Lagged Twin Study. Diabetes 2022; 71:2804-2817. [PMID: 36170668 DOI: 10.2337/db22-0513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Accepted: 09/20/2022] [Indexed: 01/11/2023]
Abstract
Investigators of previous cross-sectional epigenome-wide association studies (EWAS) in adults have reported hundreds of 5'-cytosine-phosphate-guanine-3' (CpG) sites associated with type 2 diabetes mellitus (T2DM) and glycemic traits. However, the results from EWAS have been inconsistent, and longitudinal observations of these associations are scarce. Furthermore, few studies have investigated whether DNA methylation (DNAm) could be modified by smoking, drinking, and glycemic traits, which have broad impacts on genome-wide DNAm and result in altering the risk of T2DM. Twin studies provide a valuable tool for epigenetic studies, as twins are naturally matched for genetic information. In this study, we conducted a systematic literature search in PubMed and Embase for EWAS, and 214, 33, and 117 candidate CpG sites were selected for T2DM, HbA1c, and fasting blood glucose (FBG). Based on 1,070 twins from the Chinese National Twin Registry, 67, 17, and 16 CpG sites from previous studies were validated for T2DM, HbA1c, and FBG. Longitudinal review and blood sampling for phenotypic information and DNAm were conducted twice in 2013 and 2018 for 308 twins. A cross-lagged analysis was performed to examine the temporal relationship between DNAm and T2DM or glycemic traits in the longitudinal data. A total of 11 significant paths from T2DM to subsequent DNAm and 15 paths from DNAm to subsequent T2DM were detected, suggesting both directions of associations. For glycemic traits, we detected 17 cross-lagged associations from baseline glycemic traits to subsequent DNAm, and none were from the other cross-lagged direction, indicating that CpG sites may be the consequences, not the causes, of glycemic traits. Finally, a longitudinal mediation analysis was performed to explore the mediation effects of DNAm on the associations of smoking, drinking, and glycemic traits with T2DM. No significant mediations of DNAm in the associations linking smoking and drinking with T2DM were found. In contrast, our study suggested a potential role of DNAm of cg19693031, cg00574958, and cg04816311 in mediating the effect of altered glycemic traits on T2DM.
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Affiliation(s)
- Xuanming Hong
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zhiyu Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Weihua Cao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Jun Lv
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Canqing Yu
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Tao Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Dianjianyi Sun
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Chunxiao Liao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Yuanjie Pang
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Zengchang Pang
- Qingdao Center for Disease Control and Prevention, Qingdao, China
| | - Liming Cong
- Zhejiang Center for Disease Control and Prevention, Hangzhou, China
| | - Hua Wang
- Jiangsu Center for Disease Control and Prevention, Nanjing, China
| | - Xianping Wu
- Sichuan Center for Disease Control and Prevention, Chengdu, China
| | - Yu Liu
- Heilongjiang Center for Disease Control and Prevention, Harbin, China
| | - Wenjing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
| | - Liming Li
- Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
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11
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DENARIYAKOON SIKRIT, PUTTIPANYALEARS CHAROENCHAI, CHATAMRA KRIS, MUTIRANGURA APIWAT. Breast Cancer Sera Changes in Alu Element Methylation Predict Metastatic Disease Progression. CANCER DIAGNOSIS & PROGNOSIS 2022; 2:731-738. [PMID: 36340456 PMCID: PMC9628142 DOI: 10.21873/cdp.10168] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 09/19/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND/AIM During metastatic disease development, the cancer-immune system crosstalk induces epigenetic modifications to immune cells, impairing their functions. Recently, Alu elements methylation changes were widely studied in terms of early cancer detection. This study aimed to demonstrate in vitro Alu element methylation changes in peripheral immune cells in a metastatic setting and examine their prognostic values in metastatic breast cancer. MATERIALS AND METHODS Sera from sixteen metastatic cancer patients and sixteen healthy participants were obtained and used to culture normal peripheral immune cells. After 48 h of incubation, the percentage and pattern of Alu element methylation were examined for clinical relevance. RESULTS We found that the Alu element hypomethylation was affected by age in the cancer group. Intriguingly, a decrease in Alu element methylation was found in patients with early progressive disease. Moreover, an increase in unmethylated cytosine (mCuC) loci was related to the poorer prognosis group. Accordingly, the decrease in Alu element methylation and the increase in mCuC loci pattern in peripheral immune cells correlated with poorer prognosis and early progression in metastatic breast cancer. CONCLUSION Alu element hypomethylation in immune cells and their increased mCuC foci were related to the early progression of breast cancer. These warrant the use of Alu element methylation changes for diagnostic and therapeutic purposes in breast cancer.
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Affiliation(s)
- SIKRIT DENARIYAKOON
- Queen Sirikit Centre for Breast Cancer, The Thai Red Cross Society, Bangkok, Thailand
| | - CHAROENCHAI PUTTIPANYALEARS
- Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - KRIS CHATAMRA
- Queen Sirikit Centre for Breast Cancer, The Thai Red Cross Society, Bangkok, Thailand
| | - APIWAT MUTIRANGURA
- Center of Excellence in Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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12
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Issah I, Arko-Mensah J, Rozek LS, Zarins KR, Dwomoh D, Agyekum TP, Basu N, Batterman S, Robins TG, Fobil JN. Association between toxic and essential metals in blood and global DNA methylation among electronic waste workers in Agbogbloshie, Ghana. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:72946-72956. [PMID: 35614359 DOI: 10.1007/s11356-022-20954-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 05/16/2022] [Indexed: 06/15/2023]
Abstract
Aberrant global DNA methylation status is a known biomarker for increased disease risk, especially cancer. There is little published data on the association between toxic and essential metal mixtures and global DNA methylation in electronic waste (e-waste) workers. We aimed to establish the association between toxic and essential metals in blood and the effect of their interactions on global DNA methylation among e-waste recyclers and a reference group in Ghana. We used ICP-MS to measure the level of five metals (Se, Zn, Mn, Cd, and Pb) in the blood of 100 e-waste workers and 51 controls. We quantified blood DNA methylation levels of LINE-1 as an indicator of global DNA methylation. Cd, Mn, and Se levels were significantly higher in the reference group than in e-waste workers. Only Pb was significantly higher in the e-waste workers compared to the controls. Our linear regression analysis results showed a significant inverse association between Zn and LINE-1 DNA methylation (βZn = - 0.912; 95% CI, - 1.512, - 0.306; p = 0.003) which corresponds to a 0.009 decrease in %LINE-1 methylation (95% CI, - 0.015, - 0.003; p = 0.003) for a 1% increase in Zn concentration. Potential interactions between Cd and Zn on global DNA methylation were observed. In summary, co-exposure to toxic and essential metals is associated with global (LINE-1) DNA methylation.
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Affiliation(s)
- Ibrahim Issah
- Department of Biological, Environmental and Occupational Health Sciences, School of Public Health, University of Ghana, Accra, Ghana.
| | - John Arko-Mensah
- Department of Biological, Environmental and Occupational Health Sciences, School of Public Health, University of Ghana, Accra, Ghana
| | - Laura S Rozek
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Katie R Zarins
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Duah Dwomoh
- Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana
| | - Thomas P Agyekum
- Department of Biological, Environmental and Occupational Health Sciences, School of Public Health, University of Ghana, Accra, Ghana
| | - Niladri Basu
- Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Canada
| | - Stuart Batterman
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Thomas G Robins
- Department of Environmental Health Sciences, University of Michigan, 1415 Washington Heights, Ann Arbor, MI, 48109, USA
| | - Julius N Fobil
- Department of Biological, Environmental and Occupational Health Sciences, School of Public Health, University of Ghana, Accra, Ghana
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Abstract
DNA methylation is one of the most important epigenetic modifications in breast cancer (BC) development, and long-term dietary habits can alter DNA methylation. Cadherin-4 (CDH4, a member of the cadherin family) encodes Ca2+-dependent cell-cell adhesion glycoproteins. We conducted a case-control study (380 newly diagnosed BC and 439 cancer-free controls) to explore the relationship of CDH4 methylation in peripheral blood leukocyte DNA (PBL DNA), as well as its combined and interactive effects with dietary factors on BC risk. A case-only study (335 newly diagnosed BC) was conducted to analyse the association between CDH4 methylation in breast tissue DNA and dietary factors. CDH4 methylation was detected using quantitative methylation-specific PCR. Unconditional logistic regressions were used to analyse the association of CDH4 methylation in PBL DNA and BC risk. Cross-over analysis and unconditional logistic regression were used to calculate the combined and interactive effects between CDH4 methylation in PBL DNA and dietary factors in BC. CDH4 hypermethylation was significantly associated with increased BC risk in PBL DNA (ORadjusted (ORadj) = 2·70, (95 % CI 1·90, 3·83), P < 0·001). CDH4 hypermethylation also showed significant combined effects with the consumption of vegetables (ORadj = 4·33, (95 % CI 2·63, 7·10)), allium vegetables (ORadj = 7·00, (95 % CI 4·17, 11·77)), fish (ORadj = 7·92, (95 % CI 3·79, 16·53)), milk (ORadj = 6·30, (95 % CI 3·41, 11·66)), overnight food (ORadj = 4·63, (95 % CI 2·69, 7·99)), pork (ORadj = 5·59, (95 % CI 2·94, 10·62)) and physical activity (ORadj = 4·72, (95 % CI 2·87, 7·76)). Moreover, consuming milk was significantly related with decreased risk of CDH4 methylation (OR = 0·61, (95 % CI 0·38, 0·99)) in breast tissue. Our findings may provide direct guidance on the dietary intake for specific methylated carriers to decrease their risk for developing BC.
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14
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Li L, Li S, Qin S, Gao Y, Wang C, Du J, Zhang N, Chen Y, Han Z, Yu Y, Wang F, Zhao Y. Diet, Sports, and Psychological Stress as Modulators of Breast Cancer Risk: Focus on OPRM1 Methylation. Front Nutr 2022; 8:747964. [PMID: 35024367 PMCID: PMC8744450 DOI: 10.3389/fnut.2021.747964] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023] Open
Abstract
Background: DNA methylation is influenced by environmental factors and contributes to adverse modification of cancer risk and clinicopathological features. Methods: A case-control study (402 newly diagnosed cases, 470 controls) was conducted to evaluate the effect of environmental factors and OPRM1 methylation in peripheral blood leukocyte (PBL) DNA on the risk of breast cancer. A case-only study (373 cases) was designed to evaluate the effects of environmental factors on OPRM1 methylation in tumor tissue and the relationship of methylation with clinicopathological features. Results: We found a significant association between hypermethylation of OPRM1 and the risk of breast cancer (OR = 1.914, 95%CI = 1.357–2.777). OPRM1 hypermethylation in PBL DNA combined with low intake of vegetable, garlic, soybean, poultry, and milk; high pork intake; less regular sports and a high psychological stress index significantly increased the risk of breast cancer. Soybean intake (OR = 0.425, 95%CI: 0.231–0.781) and regular sports (OR = 0.624, 95%CI: 0.399–0.976) were associated with OPRM1 hypermethylation in tumor DNA. OPRM1 hypermethylation in tumor tissue was correlated with estrogen receptor (ER) (OR = 1.945, 95%CI: 1.262–2.996) and progesterone receptor (PR) (OR = 1.611, 95%CI: 1.069–2.427) negative status; in addition, OPRM1 hypermethylation in PBL DNA was associated with human epidermal growth factor receptor 2 (HER-2) negative status (OR = 3.673, 95%CI: 1.411–9.564). Conclusion: A healthy diet, psychosocial adaptability, and regular sports are very beneficial for breast cancer prevention and progress, especially for OPRM1 hypermethylation carriers. Personalized treatment considering the correlation between OPRM1 hypermethylation and ER and PR status may provide a novel benefit for breast cancer patients.
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Affiliation(s)
- Liangliang Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Shuo Li
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Shidong Qin
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Yu Gao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Chao Wang
- The Second Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Jinghang Du
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Nannan Zhang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Yanbo Chen
- The Third Affiliated Hospital of Harbin Medical University, Harbin, China
| | - Zhen Han
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Yue Yu
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Fan Wang
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
| | - Yashuang Zhao
- Department of Epidemiology, School of Public Health, Harbin Medical University, Harbin, China
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15
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Siddiqui R, Maciver SK, Khan NA. Gut microbiome-immune system interaction in reptiles. J Appl Microbiol 2022; 132:2558-2571. [PMID: 34984778 DOI: 10.1111/jam.15438] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Revised: 12/12/2021] [Accepted: 12/31/2021] [Indexed: 12/17/2022]
Abstract
Reptiles are ectothermic amniotes in a world dominated by endotherms. Reptiles originated more than 300 million years ago and they often dwell in polluted environments which may expose them to pathogenic micro-organisms, radiation and/or heavy metals. Reptiles also possess greater longevity and may live much longer than similar-sized land mammals, for example, turtles, tortoises, crocodiles and tuatara are long-lived reptiles living up to 100 years or more. Many recent studies have emphasized the pivotal role of the gut microbiome on its host; thus, we postulated that reptilian gut microbiome and/or its metabolites and the interplay with their robust immune system may contribute to their longevity and overall hardiness. Herein, we discuss the composition of the reptilian gut microbiome, immune system-gut microbiome cross-talk, antimicrobial peptides, reptilian resistance to infectious diseases and cancer, ageing, as well the current knowledge of the genome and epigenome of these remarkable species. Preliminary studies have demonstrated that microbial gut flora of reptiles such as crocodiles, tortoises, water monitor lizard and python exhibit remarkable anticancer and antibacterial properties, as well as comprise novel gut bacterial metabolites and antimicrobial peptides. The underlying mechanisms between the gut microbiome and the immune system may hold clues to developing new therapies overall for health, and possible extrapolation to exploit the ancient defence systems of reptiles for Homo sapiens benefit.
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Affiliation(s)
- Ruqaiyyah Siddiqui
- College of Arts and Sciences, American University of Sharjah, Sharjah, United Arab Emirates
| | - Sutherland K Maciver
- Centre for Discovery Brain Science, Edinburgh Medical School, Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Naveed Ahmed Khan
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
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Siddiqui R, Maciver S, Elmoselhi A, Soares NC, Khan NA. Longevity, cellular senescence and the gut microbiome: lessons to be learned from crocodiles. Heliyon 2021; 7:e08594. [PMID: 34977412 PMCID: PMC8688568 DOI: 10.1016/j.heliyon.2021.e08594] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 11/24/2021] [Accepted: 12/09/2021] [Indexed: 12/13/2022] Open
Abstract
Crocodiles are flourishing large-bodied ectotherms in a world dominated by endotherms. They survived the Cretaceous extinction event, that eradicated the dinosaurs who are thought to be their ancestral hosts. Crocodiles reside in polluted environments; and often inhabit water which contains heavy metals; frequent exposure to radiation; feed on rotten meat and considered as one of the hardy species that has successfully survived on this planet for millions of years. Another capability that crocodiles possess is their longevity. Crocodiles live much longer than similar-sized land mammals, sometimes living up to 100 years. But how do they withstand such harsh conditions that are detrimental to Homo sapiens? Given the importance of gut microbiome on its' host physiology, we postulate that the crocodile gut microbiome and/or its' metabolites produce substances contributing to their "hardiness" and longevity. Thus, we accomplished literature search in PubMed, Web of Science and Google Scholar and herein, we discuss the composition of the crocodile gut microbiome, longevity and cellular senescence in crocodiles, their resistance to infectious diseases and cancer, and our current knowledge of the genome and epigenome of these remarkable species. Furthermore, preliminary studies that demonstrate the remarkable properties of crocodile gut microbial flora are discussed. Given the profound role of the gut microbiome in the health of its' host, it is likely that the crocodile gut microbiome and its' metabolites may be contributing to their extended life expectancy and elucidating the underlying mechanisms and properties of these metabolites may hold clues to developing new treatments for age-related diseases for the benefit of Homo sapiens.
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Affiliation(s)
- Ruqaiyyah Siddiqui
- College of Arts and Sciences, American University of Sharjah, University City, Sharjah 26666, United Arab Emirates
| | - Sutherland Maciver
- Centre for Discovery Brain Sciences, Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh, UK
| | - Adel Elmoselhi
- College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Nelson Cruz Soares
- College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
- Sharjah Institute for Medical Research, University of Sharjah, Sharjah, 27272, United Arab Emirates
| | - Naveed Ahmed Khan
- College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
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17
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Rykov SV, Filippova EA, Loginov VI, Braga EA. Gene Methylation in Circulating Cell-Free DNA from the Blood Plasma as Prognostic and Predictive Factor in Breast Cancer. RUSS J GENET+ 2021. [DOI: 10.1134/s1022795421110120] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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18
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Awada Z, Bouaoun L, Nasr R, Tfayli A, Cuenin C, Akika R, Boustany RM, Makoukji J, Tamim H, Zgheib NK, Ghantous A. LINE-1 methylation mediates the inverse association between body mass index and breast cancer risk: A pilot study in the Lebanese population. ENVIRONMENTAL RESEARCH 2021; 197:111094. [PMID: 33839117 DOI: 10.1016/j.envres.2021.111094] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 02/28/2021] [Accepted: 03/24/2021] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Lebanon is among the top countries worldwide in combined incidence and mortality of breast cancer, which raises concern about risk factors peculiar to this country. The underlying molecular mechanisms of breast cancer require elucidation, particularly epigenetics, which is recognized as a molecular sensor to environmental exposures. PURPOSE We aim to explore whether DNA methylation levels of AHRR (marker of cigarette smoking), SLC1A5 and TXLNA (markers of alcohol consumption), and LINE-1 (a genome-wide repetitive retrotransposon) can act as molecular mediators underlying putative associations between breast cancer risk and pertinent extrinsic (tobacco smoking and alcohol consumption) and intrinsic factors [age and body mass index (BMI)]. METHODS This is a cross-sectional pilot study which includes breast cancer cases (N = 65) and controls (N = 54). DNA methylation levels were measured using bisulfite pyrosequencing on available peripheral blood samples (N = 119), and Multivariate Imputation by Chained Equations (MICE) was used to impute missing DNA methylation values in remaining samples. Multiple mediation analysis was performed to assess direct and indirect (via DNA methylation) effects of intrinsic and extrinsic factors on breast cancer risk. RESULTS In relation to exposure, AHRR hypo-methylation was associated with cigarette but not waterpipe smoking, suggesting potentially different biomarkers of these two forms of tobacco use; SLC1A5 and TXLNA methylation were not associated with alcohol consumption; LINE-1 methylation was inversely associated with BMI (β-value [95% confidence interval (CI)] = -0.04 [-0.07, -0.02]), which remained significant after adjustment for age, smoking and alcohol consumption. In relation to breast cancer, there was no detectable association between AHRR, SLC1A5 or TXLNA methylation and cancer risk, but LINE-1 methylation was significantly higher in breast cancer cases when compared to controls (mean ± SD: 72.00 ± 0.66 versus 70.89 ± 0.73, P = 4.67 × 10-14). This difference remained significant after adjustment for confounders (odds ratio (OR) [95% CI] = 9.75[3.74, 25.39]). Moreover, LINE-1 hypo-methylation mediated 83% of the inverse effect of BMI on breast cancer risk. CONCLUSION This pilot study demonstrates that alterations in blood LINE-1 methylation mediate the inverse effect of BMI on breast cancer risk. This warrants large scale studies and stratification based on clinic-pathological types of breast cancer.
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Affiliation(s)
- Zainab Awada
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon; International Agency for Research on Cancer, Lyon, France
| | | | - Rihab Nasr
- Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Arafat Tfayli
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Cyrille Cuenin
- International Agency for Research on Cancer, Lyon, France
| | - Reem Akika
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Rose-Mary Boustany
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine, Beirut, Lebanon; Department of Neurology, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Joelle Makoukji
- Department of Biochemistry and Molecular Genetics, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Hani Tamim
- Department of Internal Medicine and Clinical Research Institute, American University of Beirut Faculty of Medicine, Beirut, Lebanon
| | - Nathalie K Zgheib
- Department of Pharmacology and Toxicology, American University of Beirut Faculty of Medicine, Beirut, Lebanon.
| | - Akram Ghantous
- International Agency for Research on Cancer, Lyon, France.
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19
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Barone G, De Giudici G, Gimeno D, Lanzafame G, Podda F, Cannas C, Giuffrida A, Barchitta M, Agodi A, Mazzoleni P. Surface reactivity of Etna volcanic ash and evaluation of health risks. THE SCIENCE OF THE TOTAL ENVIRONMENT 2021; 761:143248. [PMID: 33183826 DOI: 10.1016/j.scitotenv.2020.143248] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Revised: 10/19/2020] [Accepted: 10/19/2020] [Indexed: 06/11/2023]
Abstract
This work is a part of a research project conducted in order to characterize the volcanic ash from Mount Etna, focusing in particular on the surface reactivity of ashes and possible consequence for human health. In this framework, a sampling campaign began on 16 March 2013, taking advantage of the intense volcanic activity on Etna. The interaction between volcanic ash and human organism was simulated treating two classes of representative Etnean particles with ultrapure water (grainsize of 850 um) and Gamble's solution mimic lug fluids (grainsize <38 μm) with the aim to evaluate the risk due to gastric and respiratory exposure to volcanic particles. The leachates were analysed by Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES), Inductively Coupled Plasma Mass Spectrometry (ICP-MS) and Ionic Chromatography (CI) in order to highlight possible dangerous elements released in water solutions according to USGS protocol. Analyses of Gamble's solution highlighted a release of elements smaller than in watery solutions and always below the thresholds established by the Italian law. On the contrary, analyses of watery solutions evidenced, for some elements (B, Cd, Ni and As), levels higher than permitted by Italian law. Considering the effects of these elements on human health, further investigations are necessary and currently carried out in order to better constrain the release process and the specific effects on human organism.
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Affiliation(s)
- Germana Barone
- University of Catania, Department of Biological, Geological and Environmental Sciences, Corso Italia 57, 95129 Catania, Italy
| | - Giovanni De Giudici
- University of Cagliari, Department of Chemical and Geological Sciences, Universitary Campus, 09042 Monserrato, CA, Italy
| | - Domingo Gimeno
- Universitat de Barcelona, Departament de Mineralogia, Petrologia i Geologia Aplicada, Facultat de Ciències de la Terra, C/ Martí i Franquès s/n, 08028 Barcelona, Spain
| | - Gabriele Lanzafame
- University of Catania, Department of Biological, Geological and Environmental Sciences, Corso Italia 57, 95129 Catania, Italy
| | - Francesca Podda
- University of Cagliari, Department of Chemical and Geological Sciences, Universitary Campus, 09042 Monserrato, CA, Italy
| | - Carla Cannas
- University of Cagliari, Department of Chemical and Geological Sciences, Universitary Campus, 09042 Monserrato, CA, Italy
| | | | - Martina Barchitta
- University of Catania, Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", Via S. Sofia, 87, 95123 Catania, Italy
| | - Antonella Agodi
- University of Catania, Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", Via S. Sofia, 87, 95123 Catania, Italy
| | - Paolo Mazzoleni
- University of Catania, Department of Biological, Geological and Environmental Sciences, Corso Italia 57, 95129 Catania, Italy.
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20
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Maugeri A. The Effects of Dietary Interventions on DNA Methylation: Implications for Obesity Management. Int J Mol Sci 2020; 21:ijms21228670. [PMID: 33212948 PMCID: PMC7698434 DOI: 10.3390/ijms21228670] [Citation(s) in RCA: 10] [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: 10/02/2020] [Revised: 10/28/2020] [Accepted: 11/16/2020] [Indexed: 12/13/2022] Open
Abstract
Previous evidence from in vivo and observational research suggested how dietary factors might affect DNA methylation signatures involved in obesity risk. However, findings from experimental studies are still scarce and, if present, not so clear. The current review summarizes studies investigating the effect of dietary interventions on DNA methylation in the general population and especially in people at risk for or with obesity. Overall, these studies suggest how dietary interventions may induce DNA methylation changes, which in turn are likely related to the risk of obesity and to different response to weight loss programs. These findings might explain the high interindividual variation in weight loss after a dietary intervention, with some people losing a lot of weight while others much less so. However, the interactions between genetic, epigenetic, environmental and lifestyle factors make the whole framework even more complex and further studies are needed to support the hypothesis of personalized interventions against obesity.
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Affiliation(s)
- Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, 95123 Catania, Italy
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21
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Wielsøe M, Tarantini L, Bollati V, Long M, Bonefeld‐Jørgensen EC. DNA methylation level in blood and relations to breast cancer, risk factors and environmental exposure in Greenlandic Inuit women. Basic Clin Pharmacol Toxicol 2020; 127:338-350. [PMID: 32352194 PMCID: PMC7540549 DOI: 10.1111/bcpt.13424] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/23/2020] [Accepted: 04/24/2020] [Indexed: 01/22/2023]
Abstract
Several studies have found aberrant DNA methylation levels in breast cancer cases, but factors influencing DNA methylation patterns and the mechanisms are not well understood. This case-control study evaluated blood methylation level of two repetitive elements and selected breast cancer-related genes in relation to breast cancer risk, and the associations with serum level of persistent organic pollutants (POPs) and breast cancer risk factors in Greenlandic Inuit. DNA methylation was determined using bisulphite pyrosequencing in blood from 74 breast cancer cases and 80 controls. Using first tertile as reference, the following was observed. Positive associations for ATM in second tertile (OR: 2.33, 95% CI: 1.04; 5.23) and ESR2 in third tertile (OR: 2.22, 95% CI: 0.97; 5.05) suggest an increased breast cancer risk with high DNA methylation. LINE-1 methylation was lower in cases than controls. In third tertile (OR: 0.42, 95% CI: 0.18; 0.98), associations suggest in accordance with the literature an increased risk of breast cancer with LINE-1 hypomethylation. Among controls, significant associations between methylation levels and serum level of POPs and breast cancer risk factors (age, body mass index, cotinine level) were found. Thus, breast cancer risk factors and POPs may alter the risk through changes in methylation levels; further studies are needed to elucidate the mechanisms.
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Affiliation(s)
- Maria Wielsøe
- Department of Public HealthCentre for Arctic Health & Molecular EpidemiologyAarhus UniversityAarhus CDenmark
| | - Letizia Tarantini
- EPIGET – Epidemiology, Epigenetics and Toxicology LaboratoryDepartment of Clinical Sciences and Community HealthUniversità degli Studi di MilanoMilanItaly
| | - Valentina Bollati
- EPIGET – Epidemiology, Epigenetics and Toxicology LaboratoryDepartment of Clinical Sciences and Community HealthUniversità degli Studi di MilanoMilanItaly
| | - Manhai Long
- Department of Public HealthCentre for Arctic Health & Molecular EpidemiologyAarhus UniversityAarhus CDenmark
| | - Eva Cecilie Bonefeld‐Jørgensen
- Department of Public HealthCentre for Arctic Health & Molecular EpidemiologyAarhus UniversityAarhus CDenmark
- Greenland Center for Health ResearchUniversity of GreenlandNuukGreenland
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22
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Ghazi T, Arumugam T, Foolchand A, Chuturgoon AA. The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer. Cells 2020; 9:E2004. [PMID: 32878338 PMCID: PMC7565866 DOI: 10.3390/cells9092004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/24/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.
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Affiliation(s)
| | | | | | - Anil A. Chuturgoon
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa; (T.G.); (T.A.); (A.F.)
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23
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Maugeri A, Barchitta M. How Dietary Factors Affect DNA Methylation: Lesson from Epidemiological Studies. MEDICINA (KAUNAS, LITHUANIA) 2020; 56:E374. [PMID: 32722411 PMCID: PMC7466216 DOI: 10.3390/medicina56080374] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 02/06/2023]
Abstract
Over the past decades, DNA methylation has been proposed as a molecular mechanism underlying the positive or negative effects of diet on human health. Despite the number of studies on this topic is rapidly increasing, the relationship between dietary factors, changes in DNA methylation and health outcomes remains unclear. In this review, we summarize the literature from observational studies (cross-sectional, retrospective, or prospective) which examined the association of dietary factors (nutrients, foods, and dietary patterns) with DNA methylation markers among diseased or healthy people during the lifetime. Next, we discuss the methodological pitfalls by examining strengths and limitations of published studies. Finally, we close with a discussion on future challenges of this field of research, raising the need for large-size prospective studies evaluating the association between diet and DNA methylation in health and diseases for appropriate public health strategies.
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Affiliation(s)
- Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, 95123 Catania, Italy;
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24
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Donovan MG, Wren SN, Cenker M, Selmin OI, Romagnolo DF. Dietary fat and obesity as modulators of breast cancer risk: Focus on DNA methylation. Br J Pharmacol 2020; 177:1331-1350. [PMID: 31691272 DOI: 10.1111/bph.14891] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Revised: 09/23/2019] [Accepted: 09/24/2019] [Indexed: 12/13/2022] Open
Abstract
Breast cancer (BC) is the most common cancer and second leading cause of cancer mortality in women worldwide. Validated biomarkers enhance efforts for early detection and treatment, which reduce the risk of mortality. Epigenetic signatures have been suggested as good biomarkers for early detection, prognosis and targeted therapy of BC. Here, we highlight studies documenting the modifying effects of dietary fatty acids and obesity on BC biomarkers associated with DNA methylation. We focus our analysis on changes elicited in writers of DNA methylation (i.e., DNA methyltransferases), global DNA methylation and gene-specific DNA methylation. To provide context, we precede this discussion with a review of the available evidence for an association between BC incidence and both dietary fat consumption and obesity. We also include a review of well-vetted BC biomarkers related to cytosine-guanine dinucleotides methylation and how they influence BC risk, prognosis, tumour characteristics and response to treatment. LINKED ARTICLES: This article is part of a themed section on The Pharmacology of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.6/issuetoc.
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Affiliation(s)
- Micah G Donovan
- Interdisciplinary Cancer Biology Graduate Program, University of Arizona, Tucson, Arizona
| | - Spencer N Wren
- Department of Nutritional Sciences, University of Arizona, Tucson, Arizona
| | - Mikia Cenker
- Department of Nutritional Sciences, University of Arizona, Tucson, Arizona
| | - Ornella I Selmin
- Department of Nutritional Sciences, University of Arizona, Tucson, Arizona.,The University of Arizona Cancer Center, Tucson, Arizona
| | - Donato F Romagnolo
- Department of Nutritional Sciences, University of Arizona, Tucson, Arizona.,The University of Arizona Cancer Center, Tucson, Arizona
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25
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Zeng M, Zhen J, Zheng X, Qiu H, Xu X, Wu J, Lin Z, Hu J. The Role of DNA Methylation in Ischemic Stroke: A Systematic Review. Front Neurol 2020; 11:566124. [PMID: 33193003 PMCID: PMC7652818 DOI: 10.3389/fneur.2020.566124] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 09/28/2020] [Indexed: 02/05/2023] Open
Abstract
Background: Knowledge about the classic risk and protective factors of ischemic stroke is accumulating, but the underlying pathogenesis has not yet been fully understood. As emerging evidence indicates that DNA methylation plays a role in the pathological process of cerebral ischemia, this study aims to summarize the evidence of the association between DNA methylation and ischemic stroke. Methods: MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials were searched for eligible studies. The results reported by each study were summarized narratively. Results: A total of 20 studies with 7,014 individuals finally met the inclusion criteria. Three studies focused on global methylation, 11 studies on candidate-gene methylation, and six on epigenome-wide methylation analysis. Long-interspersed nuclear element 1 was found to be hypomethylated in stroke cases in two studies. Another 16 studies reported 37 genes that were differentially methylated between stroke cases and controls. Individuals with ischemic stroke were also reported to have higher acceleration in Hanuum 's epigenetic age compared to controls. Conclusion: DNA methylation might be associated with ischemic stroke and play a role in several pathological pathways. It is potentially a promising biomarker for stroke prevention, diagnosis and treatment, but the current evidence is limited by sample size and cross-sectional or retrospective design. Therefore, studies on large asymptomatic populations with the prospective design are needed to validate the current evidence, explore new pathways and identify novel risk/protective loci.
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Affiliation(s)
- Minyan Zeng
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Juanying Zhen
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Xiaodan Zheng
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Department of Clinical Medicine, Shantou University Medical College, Shantou, China
| | - Hongyan Qiu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Xiaonan Xu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Jun Wu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
| | - Zhijian Lin
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- *Correspondence: Zhijian Lin
| | - Jun Hu
- Department of Neurology, Peking University Shenzhen Hospital, Shenzhen, China
- Jun Hu
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26
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Pasha HA, Rezk NA, Riad MA. Circulating Cell Free Nuclear DNA, Mitochondrial DNA and Global DNA Methylation: Potential Noninvasive Biomarkers for Breast Cancer Diagnosis. Cancer Invest 2019; 37:432-439. [PMID: 31516038 DOI: 10.1080/07357907.2019.1663864] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Eighty seven women with benign breast lesion, 120 patients with breast cancer (BC) and one hundred controls were included in the study. Quantification of mtDNA and nDNA was done by qPCR. Global DNA methylation was measured using ELISA. Circulating cell-free nDNA and mtDNA were significantly elevated in BC and benign breast lesions patients. Global methylation was significantly low in BC patients. Combining the studied parameters in one panel, nDNA/mtDNA/hypomethylation, improved their sensitivity in detecting BC to reach 92.5%. Circulating cell-free nDNA, mtDNA and global DNA hypomethylation can be used as diagnostic and prognostic markers for BC.
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Affiliation(s)
- Heba A Pasha
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
| | - Noha A Rezk
- Medical Biochemistry Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
| | - Mohamed A Riad
- Surgery Department, Faculty of Medicine, Zagazig University , Zagazig , Egypt
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27
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Dietary vegetable intake is inversely associated with ATP-binding cassette protein A1 (ABCA1) DNA methylation levels among Japanese women. Nutrition 2019; 65:1-5. [DOI: 10.1016/j.nut.2019.02.010] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/21/2019] [Accepted: 02/14/2019] [Indexed: 11/20/2022]
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28
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Sharma A, Jamil MA, Nuesgen N, Dauksa A, Gulbinas A, Schulz WA, Oldenburg J, El-Maarri O. Detailed methylation map of LINE-1 5'-promoter region reveals hypomethylated CpG hotspots associated with tumor tissue specificity. Mol Genet Genomic Med 2019; 7:e601. [PMID: 30955237 PMCID: PMC6503062 DOI: 10.1002/mgg3.601] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 12/30/2018] [Accepted: 01/09/2019] [Indexed: 11/25/2022] Open
Abstract
Background Long interspersed nuclear elements (LINE‐1) sequences constitute a substantial portion of the human genome, and their methylation often correlating with global genomic methylation. Previous studies have highlighted the feasibility of using LINE‐1 methylation to discriminate tumors from healthy tissues. However, most studies are based on only a few specific LINE‐1 CpG sites. Methods Herein, we have performed a systematic fine‐scale analysis of methylation at 14 CpGs located in the 5′‐region of consensus LINE‐1, in bladder, colon, prostate, and gastric tumor tissues using a global degenerate approach. Results Our results reveal variable methylation levels between different CpGs, as well as some tissue‐specific differences. Trends toward hypomethylation were observed in all tumors types to certain degrees, showing statistically significance in bladder and prostate tumors. Our data points toward the presence of unique LINE‐1 DNA methylation patterns for each tumor type and tissue, indicating that not the same CpGs will be informative for testing in all tumor types. Conclusion This study provides an accurate guide that will help to design further assays that could avoid artifacts and explain the variability of obtained LINE‐1 methylation values between different studies.
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Affiliation(s)
- Amit Sharma
- Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany.,Department of Neurology, University Clinic Bonn, Bonn, Germany
| | - Muhammad A Jamil
- Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany
| | - Nicole Nuesgen
- Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany
| | - Albertas Dauksa
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Antanas Gulbinas
- Institute for Digestive Research, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Wolfgang A Schulz
- Department of Urology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Johannes Oldenburg
- Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany
| | - Osman El-Maarri
- Institute of Experimental Hematology and Transfusion Medicine, Bonn, Germany.,Department of Natural Sciences, Lebanese American University, Beirut, Lebanon
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29
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Epiphanio TMF, Fernandes NCCDA, de Oliveira TF, Lopes PA, Réssio RA, Gonçalves S, Scattone NV, Tedardi MV, Kulikowski LD, Damasceno J, Loureiro APDM, Dagli MLZ. Global DNA methylation of peripheral blood leukocytes from dogs bearing multicentric non-Hodgkin lymphomas and healthy dogs: A comparative study. PLoS One 2019; 14:e0211898. [PMID: 30908498 PMCID: PMC6433272 DOI: 10.1371/journal.pone.0211898] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Accepted: 01/22/2019] [Indexed: 12/31/2022] Open
Abstract
Non-Hodgkin lymphomas are among the most common types of tumors in dogs, and they are currently accepted as comparative models of the disease in humans. Aberrant patterns of DNA methylation seem to play a key role in the development of hematopoietic neoplasms in humans, constitute a special mechanism of transcriptional control, and may be influenced by genetic and environmental factors. Blood leukocyte DNA global methylation has been poorly investigated in dogs. The aim of this study is to examine whether peripheral blood global DNA methylation is associated with canine multicentric lymphomas. Peripheral venous blood samples from ten healthy dogs and nine dogs bearing multicentric lymphomas were collected, and the buffy coat was separated. Global DNA methylation was analyzed by High Performance Liquid Chromatography (HPLC) and immunocytochemistry (ICC). In both analyses, leukocytes from dogs with lymphoma presented lower global DNA methylation than in healthy dogs (HPLC: p = 0.027/ 5MeCyt immunoreactivity scores: p = 0.015). Moderate correlation was observed between the results obtained by HPLC and ICC (correlation coefficient = 0.50). For the identification of differently methylated genes between both groups, the Infinium Human Methylation (HM) EPIC BeadChip (850K) was used. Of the 853,307 CpGs investigated in the microarray, there were 34,574 probes hybridized in the canine samples. From this total, significant difference was observed in the methylation level of 8433 regions, and through the homologous and orthologous similarities 525 differently methylated genes were identified between the two groups. This study is pioneer in suggesting that dogs bearing non-Hodgkin lymphoma presented DNA global hypomethylation of circulating leukocytes compared with healthy dogs. Although canine samples were used in an assay developed specifically for human DNA, it was possible to identify differently methylated genes and our results reiterate the importance of the use of peripheral blood leukocytes in cancer research and possible new biomarkers targets.
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Affiliation(s)
| | | | - Tiago Franco de Oliveira
- Department of Pharmacoscience, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil
| | - Priscila Assis Lopes
- Veterinary Laboratory, Veterinary Image Institute, IVI, São Paulo, São Paulo, Brazil
| | | | - Simone Gonçalves
- Veterinary Hemotherapy Center, Hemovet, São Paulo, São Paulo, Brazil
| | - Náyra Villar Scattone
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Marcello Vannucci Tedardi
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | | | - Jullian Damasceno
- Cytogenomic Laboratory, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Ana Paula de Melo Loureiro
- Department of Clinical and Toxicological Analysis, University of São Paulo, São Paulo, São Paulo, Brazil
| | - Maria Lucia Zaidan Dagli
- Laboratory of Experimental and Comparative Oncology, Department of Pathology, University of São Paulo, São Paulo, São Paulo, Brazil
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Collin LJ, McCullough LE, Conway K, White AJ, Xu X, Cho YH, Shantakumar S, Teitelbaum SL, Neugut AI, Santella RM, Chen J, Gammon MD. Reproductive characteristics modify the association between global DNA methylation and breast cancer risk in a population-based sample of women. PLoS One 2019; 14:e0210884. [PMID: 30763347 PMCID: PMC6375664 DOI: 10.1371/journal.pone.0210884] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 01/03/2019] [Indexed: 12/29/2022] Open
Abstract
DNA methylation has been implicated in breast cancer aetiology, but little is known about whether reproductive history and DNA methylation interact to influence carcinogenesis. This study examined modification of the association between global DNA methylation and breast cancer risk by reproductive characteristics. A population-based case-control study assessed reproductive history in an interviewer-administered questionnaire. Global DNA methylation was measured from white blood cell DNA using luminometric methylation assay (LUMA) and pyrosequencing assay (long interspersed elements-1 (LINE-1). We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs) among 1 070 breast cancer cases and 1 110 population-based controls. Effect modification was assessed on additive and multiplicative scales. LUMA methylation was associated with elevated breast cancer risk across all strata (comparing the highest to the lowest quartile), but estimates were higher among women with age at menarche ≤12 years (OR = 2.87, 95%CI = 1.96–4.21) compared to >12 years (OR = 1.66, 95%CI = 1.20–2.29). We observed a 2-fold increase in the LUMA methylation-breast cancer association among women with age at first birth >23 years (OR = 2.62, 95%CI = 1.90–3.62) versus ≤23 years (OR = 1.32, 95% CI = 0.84–2.05). No modification was evident for parity or lactation. Age at menarche and age at first birth may be modifiers of the association between global DNA methylation and breast cancer risk.
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Affiliation(s)
- Lindsay J. Collin
- Department of Epidemiology, Emory University, Atlanta, GA, United States of America
- * E-mail:
| | - Lauren E. McCullough
- Department of Epidemiology, Emory University, Atlanta, GA, United States of America
| | - Kathleen Conway
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States of America
| | - Alexandra J. White
- Epidemiology Branch, National Institute of Environmental Health Science, Research Triangle Park, NC, United States of America
| | - Xinran Xu
- Roche Product Development in Asia-Pacific, Shanghai, China
| | - Yoon Hee Cho
- Department of Biomedical and Pharmaceutical Sciences, University of Montana, Missoula, MT, United States of America
| | | | - Susan L. Teitelbaum
- Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Alfred I. Neugut
- Department of Epidemiology, Columbia University, New York, NY,United States of America
- Department of Medicine, Columbia University, New York, NY, United States of America
| | - Regina M. Santella
- Department of Environmental Health, Columbia University, New York, NY, United States of America
| | - Jia Chen
- Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
- Department of Oncological Science, Icahn School of Medicine at Mount Sinai, New York, NY, United States of America
| | - Marilie D. Gammon
- Department of Epidemiology, University of North Carolina, Chapel Hill, NC, United States of America
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Barchitta M, Maugeri A, Quattrocchi A, Barone G, Mazzoleni P, Catalfo A, De Guidi G, Iemmolo MG, Crimi N, Agodi A. Mediterranean Diet and Particulate Matter Exposure Are Associated With LINE-1 Methylation: Results From a Cross-Sectional Study in Women. Front Genet 2018; 9:514. [PMID: 30425730 PMCID: PMC6218419 DOI: 10.3389/fgene.2018.00514] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Accepted: 10/12/2018] [Indexed: 11/30/2022] Open
Abstract
Emerging evidence suggests that air pollution increases the risk of cardiovascular disease (CVD) and metabolic disorders, adding to the global burden of disease attributable to lifestyle and behavioral factors. Although long interspersed nucleotide elements 1 (LINE-1) methylation has been associated with these disorders, no studies have simultaneously examined the effects of diet and air pollution exposure on DNA methylation. Herein, we evaluated the association of particulate matter (PM with aerodynamic diameters of less than 10 mm) exposure and adherence to Mediterranean Diet (MD) with LINE-1 methylation. Healthy women (n = 299), aged 15 to 80 years, were enrolled in a cross-sectional study. Dietary data and adherence to MD were assessed by a Food Frequency Questionnaire (FFQ) and Mediterranean Diet Score (MDS). PM10 levels during 1-month before recruitment were recorded by monitoring stations and assigned to each woman based on their residential address and day of recruitment. LINE-1 methylation in blood samples was assessed by pyrosequencing and reported as percentage of 5-methylcytosine (5mC). The Mann–Whitney U test, Spearman’s rank correlation test and linear regression models were applied. Our results demonstrated, for the first time, an inverse association between adherence to MD and exposure to PM10 with LINE-1 methylation: while higher monthly PM10 exposure decreases LINE-1 methylation level (β = −0.121; p = 0.037), the adherence to MD increases it (β = 0.691; p < 0.001). MDS seemed to interact with PM10 levels (p = 0.002) on LINE-1 methylation, as such we confirmed that the effect of MD decreased with increasing PM10 levels (β = 0.657; p < 0.001 in the first tertile; β = 0.573; p < 0.001 in the second tertile; β = 0.551; p < 0.001 in the third tertile). Thus, we suggest that LINE-1 methylation is a possible mechanism underpinning environment-related health effects, and encourage further research to evaluate whether the adherence to the MD could counteract the negative effect of PM10 exposure.
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Affiliation(s)
- Martina Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, Catania, Italy
| | - Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, Catania, Italy
| | - Annalisa Quattrocchi
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, Catania, Italy
| | - Germana Barone
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Paolo Mazzoleni
- Department of Biological, Geological and Environmental Sciences, University of Catania, Catania, Italy
| | - Alfio Catalfo
- Department of Chemical Science, Section of Photochemistry and Photobiology, University of Catania, Catania, Italy
| | - Guido De Guidi
- Department of Chemical Science, Section of Photochemistry and Photobiology, University of Catania, Catania, Italy.,Research Centre for the Analysis, the Monitoring and Methodology for Environmental Risk Assessment, University of Catania, Catania, Italy
| | | | - Nunzio Crimi
- Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Antonella Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, Catania, Italy
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Li SY, Wu HC, Mai HF, Zhen JX, Li GS, Chen SJ. Microarray-based analysis of whole-genome DNA methylation profiling in early detection of breast cancer. J Cell Biochem 2018; 120:658-670. [PMID: 30203578 DOI: 10.1002/jcb.27423] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Accepted: 07/12/2018] [Indexed: 12/16/2022]
Abstract
Emerging evidence indicated that changes in DNA methylation early in breast cancer (BC) development might be clinically relevant for therapeutic decisions. Through analysis of whole-genome gene expression microarray and DNA methylation microarray, we explored genes with abnormal DNA methylation in BC for early detection. Firstly, human BC tissues and adjacent non-cancerous tissues were collected from nine BC patients. Gene expression microarray sequencing was conducted for identifying differentially expressed genes and DNA methylation microarray sequencing for differentially methylated genes in BC. Differentially expressed genes and methylated genes in BC were further explored using the Cancer Genome Atlas database. The correlation between DNA methylation and gene expression was illustrated by multiple comparisons. In other 60 clinical samples, methylation specific polymerase chain reaction (PCR) and reverse transcription quantitative PCR were applied for the methylation of HOXA4 and IGF1 genes in BC and adjacent non-cancerous tissues. In total, 1680 upregulated genes and 1249 downregulated genes were determined in BC. Chromosome 16 and 17 showed more differentially methylated genes, and DNA methylation level was increased in BC tissues in each gene region. Chromosome 19 showed more differentially methylated genes, and DNA methylation level was increased in BC tissues in the exoniensis 1, untranslated region-5 and transcriptional start site 200 gene regions. In other 60 clinical samples, HOXA4 and IGF1 in BC tissues presented increased DNA methylation and decreased gene expression in BC. MCF7 cells treated with RG108 showed decreased HOXA4 and IGF1 expressions. It was estimated that HOXA4 and IGF1 were identified with increased DNA methylation and decreased gene expression in BC, which may serve as biomarkers in early BC detection.
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Affiliation(s)
- Shao-Ying Li
- Department of Thyroid and Breast Surgery, Baoan Maternal and Child Health Hospital, Jinan University, Sanming Project of Medicine in Shenzhen (SZSM201606088), Shenzhen, China
| | - Hua-Cong Wu
- Department of Thyroid and Breast Surgery, Baoan Maternal and Child Health Hospital, Jinan University, Sanming Project of Medicine in Shenzhen (SZSM201606088), Shenzhen, China
| | - Hui-Fen Mai
- Department of Thyroid and Breast Surgery, Baoan Maternal and Child Health Hospital, Jinan University, Sanming Project of Medicine in Shenzhen (SZSM201606088), Shenzhen, China
| | - Jian-Xin Zhen
- Department of Thyroid and Breast Surgery, Baoan Maternal and Child Health Hospital, Jinan University, Sanming Project of Medicine in Shenzhen (SZSM201606088), Shenzhen, China
| | - Gui-Sen Li
- Department of Thyroid and Breast Surgery, Baoan Maternal and Child Health Hospital, Jinan University, Sanming Project of Medicine in Shenzhen (SZSM201606088), Shenzhen, China
| | - Shao-Jun Chen
- Department of Breast Surgery, Shenzhen Maternal and Child Health Hospital, Shenzhen, China
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Boyne DJ, O'Sullivan DE, Olij BF, King WD, Friedenreich CM, Brenner DR. Physical Activity, Global DNA Methylation, and Breast Cancer Risk: A Systematic Literature Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2018; 27:1320-1331. [PMID: 29991518 DOI: 10.1158/1055-9965.epi-18-0175] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 04/16/2018] [Accepted: 07/04/2018] [Indexed: 11/16/2022] Open
Abstract
The extent to which physical activity reduces breast cancer risk through changes in global DNA methylation is unknown. We systematically identified studies that investigated the association between: (i) physical activity and global DNA methylation; or (ii) global DNA methylation and breast cancer risk. Associations were quantified using random-effects models. Heterogeneity was investigated through subgroup analyses and the Q-test and I 2 statistics. Twenty-four studies were reviewed. We observed a trend between higher levels of physical activity and higher levels of global DNA methylation [pooled standardized mean difference = 0.19; 95% confidence interval (CI), -0.03-0.40; P = 0.09] which, in turn, had a suggestive association with a reduced breast cancer risk (pooled relative risk = 0.70; 95% CI, 0.49-1.02; P = 0.06). In subgroup analyses, a positive association between physical activity and global DNA methylation was observed among studies assessing physical activity over long periods of time (P = 0.02). Similarly, the association between global DNA methylation and breast cancer was statistically significant for prospective cohort studies (P = 0.007). Despite the heterogeneous evidence base, the literature suggests that physical activity reduces the risk of breast cancer through increased global DNA methylation. This study is the first to systematically overview the complete biologic pathway between physical activity, global DNA methylation, and breast cancer. Cancer Epidemiol Biomarkers Prev; 27(11); 1320-31. ©2018 AACR.
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Affiliation(s)
- Devon J Boyne
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada.,Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Dylan E O'Sullivan
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Branko F Olij
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada.,Department of Public Health, Erasmus MC-University Medical Center Rotterdam, the Netherlands
| | - Will D King
- Department of Public Health Sciences, Queen's University, Kingston, Ontario, Canada
| | - Christine M Friedenreich
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada.,Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Darren R Brenner
- Department of Cancer Epidemiology and Prevention Research, CancerControl Alberta, Alberta Health Services, Calgary, Alberta, Canada. .,Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.,Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Zhang RN, Pan Q, Zheng RD, Mi YQ, Shen F, Zhou D, Chen GY, Zhu CY, Fan JG. Genome-wide analysis of DNA methylation in human peripheral leukocytes identifies potential biomarkers of nonalcoholic fatty liver disease. Int J Mol Med 2018; 42:443-452. [PMID: 29568887 DOI: 10.3892/ijmm.2018.3583] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 02/12/2018] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to uncover the role of leukocytic DNA methylation in the evaluation of nonalcoholic fatty liver disease (NAFLD). Patients with biopsy-proven NAFLD (n=35) and normal controls (n=30) were recruited from Chinese Han population. Their DNA methylation in peripheral leukocytes was subjected to genome-wide profiling. The association between differential methylation of CpG sites and NAFLD was further investigated on the basis of histopathological classification, bioinformatics, and pyrosequencing. A panel of 863 differentially methylated CpG sites dominated by global hypomethylation, characterized the NAFLD patients. Hypomethylated CpG sites of Acyl-CoA synthetase long-chain family member 4 (ACSL4) (cg15536552) and carnitine palmitoyltransferase 1C (CPT1C) (cg21604803) associated with the increased risk of NAFLD [cg15536552, odds ratio (OR): 11.44, 95% confidence interval (CI): 1.04‑125.37, P=0.046; cg21604803, OR: 6.57, 95% CI: 1.02-42.15, P=0.047] at cut-off β-values of <3.36 (ACSL4 cg15536552) and <3.54 (CPT1C cg21604803), respectively, after the adjustment of age, sex, body mass index (BMI) and homeostasis model assessment of insulin resistant (HOMA-IR). Their methylation levels also served as biomarkers of NAFLD (ACSL4 cg15536552, AUC: 0.80, 95% CI: 0.62-0.98, P=0.009; CPT1C cg21604803, AUC: 0.78, 95% CI: 0.65-0.91, P=0.001). Pathologically, lowered methylation level (β-values <3.26) of ACSL4 (cg15536552) conferred susceptibility to nonalcoholic steatohepatitis (NASH). Taken together, genome-wide hypomethylation of peripheral leukocytes may differentiate NAFLD patients from normal controls. The leukocytic hypomethylated ACSL4 (cg15536552) was suggested to be a biomarker for the pathological characteristics of NAFLD.
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Affiliation(s)
- Rui-Nan Zhang
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Qin Pan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Rui-Dan Zheng
- Diagnosis and Treatment Center for Liver Diseases, Zhengxing Hospital, Zhangzhou, Fujian 363000, P.R. China
| | - Yu-Qiang Mi
- Department of Infective Diseases, Tianjin Infectious Disease Hospital, Tianjin 300192, P.R. China
| | - Feng Shen
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Da Zhou
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Guang-Yu Chen
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Chan-Yan Zhu
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
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Taylor RM, Smith R, Collins CE, Mossman D, Wong-Brown MW, Chan EC, Evans TJ, Attia JR, Smith T, Butler T, Hure AJ. Methyl-Donor and Cofactor Nutrient Intakes in the First 2-3 Years and Global DNA Methylation at Age 4: A Prospective Cohort Study. Nutrients 2018; 10:E273. [PMID: 29495543 PMCID: PMC5872691 DOI: 10.3390/nu10030273] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/13/2018] [Accepted: 02/13/2018] [Indexed: 01/31/2023] Open
Abstract
BACKGROUND During the early postnatal period, the impact of nutrition on DNA methylation has not been well studied in humans. The aim was to quantify the relationship between one-carbon metabolism nutrient intake during the first three years of life and global DNA methylation levels at four years. DESIGN Childhood dietary intake was assessed using infant feeding questionnaires, food frequency questionnaires, 4-day weighed food records and 24-h food records. The dietary records were used to estimate the intake of methionine, folate, vitamins B2, B6 and B12 and choline. The accumulative nutrient intake specific rank from three months to three years of age was used for analysis. Global DNA methylation (%5-methyl cytosines (%5-mC)) was measured in buccal cells at four years of age, using an enzyme-linked immunosorbent assay (ELISA) commercial kit. Linear regression models were used to quantify the statistical relationships. RESULTS Data were collected from 73 children recruited from the Women and their Children's Health (WATCH) study. No association was found between one-carbon metabolism nutrient intake and global DNA methylation levels (P > 0.05). Global DNA methylation levels in males were significantly higher than in females (median %5-mC: 1.82 vs. 1.03, males and females respectively, (P < 0.05)). CONCLUSION No association was found between the intake of one-carbon metabolism nutrients during the early postnatal period and global DNA methylation levels at age four years. Higher global DNA methylation levels in males warrants further investigation.
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Affiliation(s)
- Rachael M. Taylor
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW 2308, Australia; (R.S.); (C.E.C.); (T.S.); (T.B.)
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
| | - Roger Smith
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW 2308, Australia; (R.S.); (C.E.C.); (T.S.); (T.B.)
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
| | - Clare E. Collins
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW 2308, Australia; (R.S.); (C.E.C.); (T.S.); (T.B.)
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Faculty of Health and Medicine, School of Health Sciences, University of Newcastle, Callaghan, NSW 2308, Australia
- Priority Research Centre in Physical Activity and Nutrition, University of Newcastle, Callaghan, NSW 2308, Australia
| | - David Mossman
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Department of Molecular Medicine, NSW Health Pathology, John Hunter Hospital, New Lambton Heights, NSW 2305, Australia
| | - Michelle W. Wong-Brown
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Faculty of Health, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia
| | - Eng-Cheng Chan
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
| | - Tiffany-Jane Evans
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Clinical Research Design IT and Statistical Support (CReDITSS) Unit, Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia
| | - John R. Attia
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Clinical Research Design IT and Statistical Support (CReDITSS) Unit, Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia
| | - Tenele Smith
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW 2308, Australia; (R.S.); (C.E.C.); (T.S.); (T.B.)
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
| | - Trent Butler
- Priority Research Centre for Reproductive Science, University of Newcastle, Callaghan, NSW 2308, Australia; (R.S.); (C.E.C.); (T.S.); (T.B.)
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
| | - Alexis J. Hure
- Faculty of Health and Medicine, School of Medicine and Public Health, University of Newcastle, Callaghan, NSW 2308, Australia; (E.-C.C.); (J.R.A.); (A.J.H.)
- Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia; (D.M.); (M.W.W.-B.); (T.-J.E.)
- Priority Research Centre for Generational, Health and Ageing, University of Newcastle, Callaghan, NSW 2308, Australia
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Passador J, Toffoli LV, Fernandes KB, Neves-Souza RD, Pelosi GG, Gomes MV. Dietary Ingestion of Calories and Micronutrients Modulates the DNA Methylation Profile of Leukocytes from Older Individuals. J Nutr Health Aging 2018; 22:1281-1285. [PMID: 30498838 DOI: 10.1007/s12603-018-1085-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Several lines of evidence from the last decade support the connection between nutrition and epigenetic mechanisms. In the present study we evaluated the impact of the daily dietary intake of calories and the micronutrients vitamin A, D, B1, B2, B5, C, E, copper, calcium, phosphorus, iron, iodine, selenium, manganese, potassium and sodium on the global DNA methylation profile of blood cells from older individuals. RESEARCH METHODS AND PROCEDURES The study enrolled 126 physically independent elderly of both sexes (60 men and 66 women). For the molecular analysis, DNA samples were extracted from leukocytes and global DNA methylation was evaluated using a high throughput Elisa-based method. Correlations between global DNA methylation and the daily intake of calorie or micronutrients were evaluated using Prism5 GraphPad Software. RESULTS A statistically significant correlation was observed between global DNA methylation and the daily caloric value (p=0.019, r=-0.21), and the intake of vitamin A (p=0.03, r=-0.18), Vitamin E (p=0.027, r=-0.20) and copper (p=0.04, r=-0.18). No correlation was observed between global DNA methylation and the daily intake of vitamin D, B1, B2, B5, C, calcium, phosphorus, iron, iodine, selenium, manganese and potassium (p>0.05). CONCLUSION Our data demonstrate that the daily intake of calories or the micronutrients vitamin A, vitamin E and copper can potentially modulate the global DNA methylation profile of leukocytes in older adults and corroborate the notion of nutritional influences on epigenetic mechanisms.
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Affiliation(s)
- J Passador
- Gislaine Garcia Pelosi, Departamento de Ciências Fisiológicas, CCB-UEL, Campus Universitário, Rod Celso Garcia Cid, Km 380, CEP 86055-900, Londrina, Paraná, Brazil. Phone.: +55 43 3371 4201; fax: +55 43 3371 4467, E-mail address:
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Dalasanur Nagaprashantha L, Adhikari R, Singhal J, Chikara S, Awasthi S, Horne D, Singhal SS. Translational opportunities for broad-spectrum natural phytochemicals and targeted agent combinations in breast cancer. Int J Cancer 2017; 142:658-670. [PMID: 28975625 DOI: 10.1002/ijc.31085] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2017] [Revised: 08/18/2017] [Accepted: 09/12/2017] [Indexed: 12/17/2022]
Abstract
Breast cancer (BC) prevention and therapy in the context of life-style risk factors and biological drivers is a major focus of developmental therapeutics in oncology. Obesity, alcohol, chronic estrogen signaling and smoking have distinct BC precipitating and facilitating effects that may act alone or in combination. A spectrum of signaling events including enhanced oxidative stress and changes in estrogen-receptor (ER)-dependent and -independent signaling drive the progression of BC. Breast tumors modulate ERα/ERβ ratio, upregulate proliferative pathways driven by ERα and HER2 with a parallel loss and/or downregulation of tumor suppressors such as TP53 and PTEN which together impact the efficacy of therapeutic strategies and frequently lead to emergence of drug resistance. Natural phytochemicals modulate oxidative stress, leptin, integrin, HER2, MAPK, ERK, Wnt/β-catenin and NFκB signaling along with regulating ERα and ERβ, thereby presenting unique opportunities for both primary and combinatorial interventions in BC. In this regard, this article focuses on critical analyses of the evidence from multiple studies on the efficacy of natural phytochemicals in BC. In addition, areas in which the combinations of such effective natural phytochemicals with approved and/or developing anticancer agents can be translationally beneficial are discussed to derive evidence-based inference for addressing challenges in BC control and therapy.
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Affiliation(s)
| | | | - Jyotsana Singhal
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Shireen Chikara
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Sanjay Awasthi
- Texas Tech University Health Sciences Center, Lubbock, TX
| | - David Horne
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
| | - Sharad S Singhal
- Department of Molecular Medicine, City of Hope National Medical Center, Duarte, CA
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Grelus A, Nica DV, Miklos I, Belengeanu V, Ioiart I, Popescu C. Clinical Significance of Measuring Global Hydroxymethylation of White Blood Cell DNA in Prostate Cancer: Comparison to PSA in a Pilot Exploratory Study. Int J Mol Sci 2017; 18:ijms18112465. [PMID: 29156615 PMCID: PMC5713431 DOI: 10.3390/ijms18112465] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Revised: 11/16/2017] [Accepted: 11/16/2017] [Indexed: 12/13/2022] Open
Abstract
This is the first study investigating the clinical relevance of 5-hydroxymethylcytosine (5hmC) in genomic DNA from white blood cells (WBC) in the context of prostate cancer (PCa) and other prostate pathologies. Using an enzyme-linked immunosorbent assay, we identified significantly different distributions of patients with low and elevated 5hmC content in WBC DNA across controls and patients with prostate cancer (PCa), atypical small acinar proliferation (ASAP), and benign prostatic hyperplasia (BPH). The measured values were within the normal range for most PCa patients, while the latter category was predominant for ASAP. We observed a wider heterogeneity in 5hmC content in all of the prostate pathologies analyzed when compared to the healthy age-matched controls. When compared to blood levels of prostate-specific antigen (PSA), this 5hmC-based biomarker had a lower performance in PCa detection than the use of a PSA cut-off of 2.5 nanograms per milliliter (ng/mL). Above this threshold, however, it delineated almost three quarters of PCa patients from controls and patients with other prostate pathologies. Overall, genome-wide 5hmC content of WBC DNA appears to be applicable for detecting non-cancerous prostate diseases, rather than PCa. Our results also suggest a potential clinical usefulness of complementing PSA as a PCa marker by the addition of a set of hydroxymethylation markers in the blood, but further studies are necessary to confirm these findings.
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Affiliation(s)
- Alin Grelus
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
- Arad County Emergency Clinical Hospital, Str. Andreny Karoly nr. 2-4, 310037 Arad, Romania.
| | - Dragos V Nica
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
| | - Imola Miklos
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
- Arad County Emergency Clinical Hospital, Str. Andreny Karoly nr. 2-4, 310037 Arad, Romania.
| | - Valerica Belengeanu
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
| | - Ioan Ioiart
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
- Arad County Emergency Clinical Hospital, Str. Andreny Karoly nr. 2-4, 310037 Arad, Romania.
| | - Cristina Popescu
- Institute of Life Sciences, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
- Faculty of Pharmacy, "Vasile Goldis" Western University of Arad, Str. Liviu Rebreanu 86, 310045 Arad, Romania.
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Han Y, Xu J, Kim J, Wu X, Gu J. LINE-1 methylation in peripheral blood leukocytes and clinical characteristics and prognosis of prostate cancer patients. Oncotarget 2017; 8:94020-94027. [PMID: 29212206 PMCID: PMC5706852 DOI: 10.18632/oncotarget.21511] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/18/2017] [Indexed: 11/25/2022] Open
Abstract
Global DNA methylation of long interspersed nucleotide elements (LINE-1) in leukocytes has been suggested to be a risk factor for a few cancers. There has been no report of LINE-1 methylation in leukocytes as a risk factor for aggressive prostate cancer at diagnosis and prognosis after treatments. In this study, we measured the leukocyte DNA methylation of LINE-1 in 795 PCa patients and compared the methylation levels across different clinical subgroups. We then determined the association of LINE-1 methylation in leukocytes with clinicopathological variables at diagnosis using logistic regression analysis and biochemical recurrence in patients receiving active treatments (prostatectomy and radiotherapy) using Cox proportional hazard model after adjusting for age, BMI, smoking status, pack year, D’Amico risk groups, and treatments. Overall, the DNA methylation of LINE-1 was not associated with the risk of being diagnosed with high-risk prostate cancer or the risk of biochemical recurrence upon active treatments. Future studies are warranted to investigate other types of repetitive element methylation and longitudinal changes of global methylation in relation to prostate cancer risk and prognosis.
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Affiliation(s)
- Yuyan Han
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Junfeng Xu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jeri Kim
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Xifeng Wu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
| | - Jian Gu
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
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Moradi Sarabi M, Ghareghani P, Khademi F, Zal F. Oral Contraceptive Use May Modulate Global Genomic DNA Methylation and Promoter Methylation of APC1 and ESR1. Asian Pac J Cancer Prev 2017; 18:2361-2366. [PMID: 28950679 PMCID: PMC5720637 DOI: 10.22034/apjcp.2017.18.9.2361] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: There are challenging reports in the public health sphere regarding associations between oral contraceptive (OC) use and cancer risk. Methods: To evaluate possible effects of OCs on cancer susceptibility, we quantified of global 5-methyl cytosine (5-mC) levels and assessed methylation patterns of CpG islands of two key tumor suppressor genes, APC1 and ESR1, in serum of users by enzyme-linked immunosorbent assay and methylation specific PCR methods, respectively. Results: Our results indicated that OCs significantly decrease the level of global DNA methylation in users relative to control non-users. However, our data revealed no significant differences between CpG island methylation patterns for ESR1 and APC1 in healthy control and OC-treated women. However, we did find a trend for hypermethylation of both tumor suppressor genes in OC users. Conclusion: Our data suggest that the level of 5-mC but not individual CpG island patterns is significantly influenced by OCs in our cross-section of adult users.
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Affiliation(s)
- Mostafa Moradi Sarabi
- Biochemistry and Genetics Department, Faculty of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran.
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41
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White blood cell DNA methylation and risk of breast cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Breast Cancer Res 2017; 19:94. [PMID: 28821281 PMCID: PMC5563066 DOI: 10.1186/s13058-017-0886-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2017] [Accepted: 07/25/2017] [Indexed: 01/24/2023] Open
Abstract
Background Several studies have suggested that global DNA methylation in circulating white blood cells (WBC) is associated with breast cancer risk. Methods To address conflicting results and concerns that the findings for WBC DNA methylation in some prior studies may reflect disease effects, we evaluated the relationship between global levels of WBC DNA methylation in white blood cells and breast cancer risk in a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) cohort. A total of 428 invasive breast cancer cases and 419 controls, frequency matched on age at entry (55–59, 60–64, 65–69, ≥70 years), year of entry (on/before September 30, 1997, on/after October 1, 1997) and period of DNA extraction (previously extracted, newly extracted) were included. The ratio of 5-methyl-2’ deoxycytidine [5-mdC] to 2’-deoxyguanine [dG], assuming [dG] = [5-mdC] + [2’-deoxycytidine [dC]] (%5-mdC), was determined by liquid chromatography-electrospray ionization-tandem mass spectrometry, an especially accurate method for assessing total genomic DNA methylation. Results Odds ratio (OR) estimates and 95% confidence intervals (CI) for breast cancer risk adjusted for age at entry, year of entry, and period of DNA extraction, were 1.0 (referent), 0.89 (95% CI, 0.6–1.3), 0.88 (95% CI, 0.6–1.3), and 0.84 (95% CI, 0.6–1.2) for women in the highest compared to lowest quartile levels of %5md-C (p for trend = .39). Effects did not meaningfully vary by time elapsed from WBC collection to diagnosis. Discussion These results do not support the hypothesis that global DNA hypomethylation in WBC DNA is associated with increased breast cancer risk prior to the appearance of clinical disease.
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Shen J, Song R, Gong Y, Zhao H. Global DNA hypomethylation in leukocytes associated with glioma risk. Oncotarget 2017; 8:63223-63231. [PMID: 28968983 PMCID: PMC5609915 DOI: 10.18632/oncotarget.18739] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Accepted: 05/21/2017] [Indexed: 11/25/2022] Open
Abstract
Global DNA hypomethylation in leukocytes has been associated with increased risk for a variety of cancers. However, the role of leukocyte global DNA hypomethylation in glioma development, if any, is largely unknown. To define this role, we performed a case-control study with 390 glioma patients and 390 controls with no known cancer. Levels of 5-methylcytosine (5-mC%), a marker for global DNA methylation, were measured in leukocyte DNA. Overall, median levels of 5-mC% were significantly lower in glioma cases than in controls (3.45 vs 3.82, P=0.001). Levels of 5-mC% differed significantly by age and sex among controls and by tumor subtype and grade among glioma cases. In multivariate analysis, lower levels of 5-mC% were associated with a 1.31-fold increased risk of glioma (odds ratio = 1.31, 95% confidence interval = 1.10-1.41). A significant dose-response trend was observed in quartile analysis (P=0.001). In an analysis further stratified by clinical characteristics at baseline, the association between lower levels of 5-mC% and glioma risk was evident only among younger participants (age <52 years), women, and those with aggressive tumor characteristics, such as glioblastoma subtype, high tumor grade (grade III or IV), and absence of IDH1 mutation. Our findings indicate that global DNA hypomethylation in leukocytes may contribute to the development of glioma and that the association is affected by age, sex, and tumor aggressiveness.
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Affiliation(s)
- Jie Shen
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Renduo Song
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ye Gong
- Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hua Zhao
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Khakpour G, Noruzinia M, Izadi P, Karami F, Ahmadvand M, Heshmat R, Amoli MM, Tavakkoly-Bazzaz J. Methylomics of breast cancer: Seeking epimarkers in peripheral blood of young subjects. Tumour Biol 2017; 39:1010428317695040. [PMID: 28349825 DOI: 10.1177/1010428317695040] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Critical roles of epigenomic alterations in the pathogenesis of breast cancer have recently seized great attentions toward finding epimarkers in either non-invasive or semi-non-invasive samples as well as peripheral blood. In this way, methylated DNA immunoprecipitation microarray (MeDIP-chip) was performed on DNA samples isolated from white blood cells of 30 breast cancer patients compared to 30 healthy controls. A total of 1799 differentially methylated regions were identified including SLC6A3, Rab40C, ZNF584, and FOXD3 whose significant methylation differences were confirmed in breast cancer patients through quantitative real-time polymerase chain reaction. Hypermethylation of APC, HDAC1, and GSK1 genes has been previously reported in more than one study on tissue samples of breast cancer. Methylation of those aforementioned genes in white blood cells of our young patients not only relies on their importance in breast cancer pathogenesis but also may highlight their potential as early epimarkers that makes further assessments necessary in large cohort studies.
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Affiliation(s)
- Golnaz Khakpour
- 1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrdad Noruzinia
- 2 Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pantea Izadi
- 1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Karami
- 3 Department of Medical Genetics, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mohammad Ahmadvand
- 4 Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ramin Heshmat
- 5 Chronic Disease Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahsa M Amoli
- 6 Metabolic Disorders Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Javad Tavakkoly-Bazzaz
- 1 Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Relationships between Global DNA Methylation in Circulating White Blood Cells and Breast Cancer Risk Factors. J Cancer Epidemiol 2017; 2017:2705860. [PMID: 28484492 PMCID: PMC5397634 DOI: 10.1155/2017/2705860] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2016] [Revised: 02/26/2017] [Accepted: 03/14/2017] [Indexed: 12/21/2022] Open
Abstract
It is not yet clear whether white blood cell DNA global methylation is associated with breast cancer risk. In this review we examine the relationships between multiple breast cancer risk factors and three markers of global DNA methylation: LINE-1, 5-mdC, and Alu. A literature search was conducted using Pubmed up to April 1, 2016, using combinations of relevant outcomes such as “WBC methylation,” “blood methylation,” “blood LINE-1 methylation,” and a comprehensive list of known and suspected breast cancer risk factors. Overall, the vast majority of reports in the literature have focused on LINE-1. There was reasonably consistent evidence across the studies examined that males have higher levels of LINE-1 methylation in WBC DNA than females. None of the other demographic, lifestyle, dietary, or health condition risk factors were consistently associated with LINE-1 DNA methylation across studies. With the possible exception of sex, there was also little evidence that the wide range of breast cancer risk factors we examined were associated with either of the other two global DNA methylation markers: 5-mdC and Alu. One possible implication of the observed lack of association between global WBC DNA methylation and known breast cancer risk factors is that the association between global WBC DNA methylation and breast cancer, if it exists, is due to a disease effect.
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45
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DUSP1 promoter methylation in peripheral blood leukocyte is associated with triple-negative breast cancer risk. Sci Rep 2017; 7:43011. [PMID: 28220843 PMCID: PMC5318948 DOI: 10.1038/srep43011] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 01/18/2017] [Indexed: 12/13/2022] Open
Abstract
DNA methylation is one of the most common epigenetic alterations, providing important information regarding cancer risk and prognosis. A case-control study (423 breast cancer cases, 509 controls) and a case-only study (326 cases) were conducted to evaluate the association of DUSP1 promoter methylation with breast cancer risk and clinicopathological characteristics. No significant association between DUSP1 methylation in peripheral blood leukocyte (PBL) DNA and breast cancer risk was observed. DUSP1 methylation was significantly associated with ER/PR-negative status; in particular, triple-negative breast cancer patients showed the highest frequency of DUSP1 methylation in both tumour DNA and PBL DNA. Soybean intake was significantly correlated with methylated DUSP1 only in ER-negative (OR 2.978; 95% CI 1.245-7.124) and PR negative (OR 2.735; 95% CI 1.315-5.692) patients. Irregular menstruation was significantly associated with methylated DUSP1 only in ER-positive (OR 3.564; 95% CI 1.691-7.511) and PR-positive (OR 3.902, 95% CI 1.656-9.194) patients. Thus, DUSP1 methylation is a cancer-associated hypermethylation event that is closely linked with triple-negative status. Further investigations are warranted to confirm the association of environmental factors, including fruit and soybean intake, irregular menstruation, and ER/PR status, with DUSP1 methylation in breast tumour DNA.
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46
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Methylome-wide Association Study of Atrial Fibrillation in Framingham Heart Study. Sci Rep 2017; 7:40377. [PMID: 28067321 PMCID: PMC5220313 DOI: 10.1038/srep40377] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Accepted: 12/05/2016] [Indexed: 12/18/2022] Open
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia, but little is known about the molecular mechanisms associated with AF arrhythmogenesis. DNA methylation is an important epigenetic mechanism that regulates gene expression and downstream biological processes. We hypothesize that DNA methylation might play an important role in the susceptibility to develop AF. A total of 2,639 participants from the Offspring Cohort of Framingham Heart Study were enrolled in the current study. These participants included 183 participants with prevalent AF and 220 with incident AF during up to 9 years follow up. Genome-wide methylation was profiled using the Illumina Infinium HumanMethylation450 BeadChip on blood-derived DNA collected during the eighth examination cycle (2005-2008). Two CpG sites were significantly associated with prevalent AF, and five CpGs were associated with incident AF after correction for multiple testing (FDR < 0.05). Fourteen previously reported genome-wide significant AF-related SNP were each associated with at least one CpG site; the most significant association was rs6490029 at the CUX2 locus and cg10833066 (P = 9.5 × 10-279). In summary, we performed genome-wide methylation profiling in a community-based cohort and identified seven methylation signatures associated with AF. Our study suggests that DNA methylation might play an important role in AF arrhythmogenesis.
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47
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Shen J, Song R, Wan J, Huff C, Fang S, Lee JE, Zhao H. Global methylation of blood leukocyte DNA and risk of melanoma. Int J Cancer 2017; 140:1503-1509. [PMID: 28006848 DOI: 10.1002/ijc.30577] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 11/10/2016] [Accepted: 12/13/2016] [Indexed: 12/15/2022]
Abstract
Global DNA methylation, possibly influenced by lifestyle and environmental factors, has been suggested to play an active role in carcinogenesis. However, its role in melanoma has rarely been explored. The aims of this study were to evaluate the relationship between melanoma risk and levels of 5-methylcytosine (5-mC), a marker for global DNA methylation, in blood leukocyte DNA, and to determine whether this 5-mC level is influenced by pigmentation and sun exposure. This case-control study included 540 melanoma cases and 540 healthy controls. Overall, melanoma cases had significantly lower levels of 5-mC% than healthy controls (median: 3.24 vs. 3.91, p < 0.001). The significant difference between two groups did not differ by pigmentation or sun exposure. Among healthy controls, however, those who had fair skin color (p = 0.041) or light or no tanning after prolonged sun exposure (p = 0.031) or used a sunlamp (p = 0.028) had lower levels of 5-mC% than their counterparts. In addition, those with an intermediate or high phenotypic index, an indicator of cutaneous cancer susceptibility, had 2.58-fold greater likelihood of having a low level of 5-mC% [odds ratio (OR): 2.58; 95% confidence interval (CI): 1.72, 3.96] than those with a low phenotypic index. Lower levels of 5-mC% were associated with a 1.25-fold greater risk of melanoma (OR: 1.25; 95% CI: 1.08, 1.37). A significant dose-response relationship was observed in quartile analysis (p = 0.001). Our results suggest that global hypomethylation in blood leukocyte DNA is associated with increased risk of melanoma and that the level of methylation is influenced by pigmentation and sun exposure.
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Affiliation(s)
- Jie Shen
- Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Renduo Song
- Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jie Wan
- Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Chad Huff
- Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Shenying Fang
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Jeffrey E Lee
- Departments of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
| | - Hua Zhao
- Departments of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030
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48
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Buj R, Mallona I, Díez-Villanueva A, Barrera V, Mauricio D, Puig-Domingo M, Reverter JL, Matias-Guiu X, Azuara D, Ramírez JL, Alonso S, Rosell R, Capellà G, Perucho M, Robledo M, Peinado MA, Jordà M. Quantification of unmethylated Alu (QUAlu): a tool to assess global hypomethylation in routine clinical samples. Oncotarget 2016; 7:10536-46. [PMID: 26859682 PMCID: PMC4891138 DOI: 10.18632/oncotarget.7233] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2015] [Accepted: 01/25/2016] [Indexed: 01/05/2023] Open
Abstract
Hypomethylation of DNA is a hallmark of cancer and its analysis as tumor biomarker has been proposed, but its determination in clinical settings is hampered by lack of standardized methodologies. Here, we present QUAlu (Quantification of Unmethylated Alu), a new technique to estimate the Percentage of UnMethylated Alu (PUMA) as a surrogate for global hypomethylation. QUAlu consists in the measurement by qPCR of Alu repeats after digestion of genomic DNA with isoschizomers with differential sensitivity to DNA methylation. QUAlu performance has been evaluated for reproducibility, trueness and specificity, and validated by deep sequencing. As a proof of use, QUAlu has been applied to a broad variety of pathological examination specimens covering five cancer types. Major findings of the preliminary application of QUAlu to clinical samples include: (1) all normal tissues displayed similar PUMA; (2) tumors showed variable PUMA with the highest levels in lung and colon and the lowest in thyroid cancer; (3) stools from colon cancer patients presented higher PUMA than those from control individuals; (4) lung squamous cell carcinomas showed higher PUMA than lung adenocarcinomas, and an increasing hypomethylation trend associated with smoking habits. In conclusion, QUAlu is a simple and robust method to determine Alu hypomethylation in human biospecimens and may be easily implemented in research and clinical settings.
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Affiliation(s)
- Raquel Buj
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Izaskun Mallona
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Anna Díez-Villanueva
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Víctor Barrera
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain
| | - Dídac Mauricio
- Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Department of Endocrinology and Nutrition, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.,ISCIII Center for Biomedical Research on Diabetes and Metabolic Associated Diseases (CIBERDEM), Madrid, Spain
| | - Manel Puig-Domingo
- Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Department of Endocrinology and Nutrition, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain.,ISCIII Center for Biomedical Research on Diabetes and Metabolic Associated Diseases (CIBERDEM), Madrid, Spain
| | - Jordi L Reverter
- Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Department of Endocrinology and Nutrition, University Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Xavier Matias-Guiu
- Department of Pathology and Molecular Genetics, University Hospital Arnau de Vilanova and University of Lleida, Biomedical Research Institute of Lleida (IRBLLEIDA), Lleida, Spain
| | - Daniel Azuara
- Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jose L Ramírez
- Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Sergio Alonso
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Rafael Rosell
- Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Catalan Institute of Oncology (ICO), Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain
| | - Gabriel Capellà
- Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Manuel Perucho
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain.,Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain.,ISCIII Center for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain
| | - Miguel A Peinado
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
| | - Mireia Jordà
- Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Badalona, Barcelona, Spain.,Germans Trias i Pujol Health Sciences Research Institute (IGTP), Badalona, Barcelona, Spain
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Tang Q, Cheng J, Cao X, Surowy H, Burwinkel B. Blood-based DNA methylation as biomarker for breast cancer: a systematic review. Clin Epigenetics 2016; 8:115. [PMID: 27895805 PMCID: PMC5109688 DOI: 10.1186/s13148-016-0282-6] [Citation(s) in RCA: 105] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 10/26/2016] [Indexed: 12/19/2022] Open
Abstract
Multiple studies have investigated global DNA methylation profiles and gene-specific DNA methylation in blood-based DNA to develop powerful screening markers for cancer. This systematic review summarizes the current evidence on methylation studies that investigated methylation level of blood-derived DNA of breast cancer (BC) patients in comparison to healthy controls by conducting a systematic literature review in PubMed and Web of Science. Essential results, such as methylation levels of BC cases and healthy controls, p values, and odds ratios, were extracted from these studies by two investigators independently. Overall, 45 publications met the inclusion criteria for this review. DNA from whole blood, as well as cell-free DNA (cfDNA) from serum or plasma, was used in these studies. The most common method used for measuring global DNA methylation was the investigation of repetitive elements as surrogates and the application of array-based genome-wide methylation analysis. For measuring gene-specific methylation level, methylation-specific PCR and pyrosequencing were the most frequently used methods. Epigenome-wide blood DNA hypomethylation in BC patients were reported in several studies; however, the evidence is still not conclusive. The most frequently investigated gene in whole blood was BRCA1, which was found more frequently methylated in patients compared to controls. RASSF1A was the most widely investigated gene in cfDNA of serum or plasma, which was also found more frequently methylated in patients compared to controls. Several of the eligible studies reported the associations of global hypomethylation and increased BC risk. Studies investigated associations between gene-specific methylation and BC risk, while got heterogeneous results. But two studies reported that hypermethylation of ATM gene was associated with increased BC risk, which suggest the potential use of this gene for BC risk stratification. Overall, our review suggests the possibility of using blood-based DNA methylation marker as promising marker for BC risk stratification, as several studies found associations between certain methylation level in blood and BC risk. However, so far, the evidence is still quite limited. Optimal markers are yet to be developed and promising results needed to be validated in prospective study cohorts and tested in large screening populations.
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Affiliation(s)
- Qiuqiong Tang
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany ; Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Jie Cheng
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany ; Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Xue Cao
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany ; Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Harald Surowy
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany ; Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara Burwinkel
- Molecular Biology of Breast Cancer, Department of Gynecology and Obstetrics, Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany ; Division of Molecular Epidemiology (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany
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50
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Girotra S, Yeghiazaryan K, Golubnitschaja O. Potential biomarker panels in overall breast cancer management: advancements by multilevel diagnostics. Per Med 2016; 13:469-484. [PMID: 29767597 DOI: 10.2217/pme-2016-0020] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Breast cancer (BC) prevalence has reached an epidemic scale with half a million deaths annually. Current deficits in BC management include predictive and preventive approaches, optimized screening programs, individualized patient profiling, highly sensitive detection technologies for more precise diagnostics and therapy monitoring, individualized prediction and effective treatment of BC metastatic disease. To advance BC management, paradigm shift from delayed to predictive, preventive and personalized medical services is essential. Corresponding step forwards requires innovative multilevel diagnostics procuring specific panels of validated biomarkers. Here, we discuss current instrumental advancements including genomics, proteomics, epigenetics, miRNA, metabolomics, circulating tumor cells and cancer stem cells with a focus on biomarker discovery and multilevel diagnostic panels. A list of the recommended biomarker candidates is provided.
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