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Zinkeng A, Taylor FL, Cheong SH, Song H, Merchant JL. Early Onset Colorectal Cancer: Molecular Underpinnings Accelerating Occurrence. Cell Mol Gastroenterol Hepatol 2024; 19:101425. [PMID: 39510499 PMCID: PMC11731505 DOI: 10.1016/j.jcmgh.2024.101425] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 10/28/2024] [Accepted: 10/28/2024] [Indexed: 11/15/2024]
Abstract
The onset of colorectal cancer (CRC) in patients younger than 50 continues to rapidly increase. This study highlights the epidemiologic changes, risk factors, clinical characteristics, and molecular profiles prevalent in early onset CRC patients, and identifies key areas for future research. It has been noted that only a small fraction of early onset CRC cases is attributed to known hereditary mutations and fit the canonical pathway of late-onset colorectal cancer development. To highlight this, we review the genetic and epigenetic modifications specific to early onset CRC. We also discuss the synergetic effect of single-nucleotide polymorphisms and environmental factors on the early onset of CRC. Additionally, we discuss the potential of noninvasive biomarker assays to enhance early detection, screening, diagnosis, and prognostic outcome predictions.
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Affiliation(s)
- Atehkeng Zinkeng
- Medical Scientist Training Program, University of Arizona College of Medicine, Tucson, Arizona
| | | | | | | | - Juanita L Merchant
- Department of Medicine, University of Arizona College of Medicine, Tucson, Arizona.
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2
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Postwala H, Shah Y, Parekh PS, Chorawala MR. Unveiling the genetic and epigenetic landscape of colorectal cancer: new insights into pathogenic pathways. Med Oncol 2023; 40:334. [PMID: 37855910 DOI: 10.1007/s12032-023-02201-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/19/2023] [Indexed: 10/20/2023]
Abstract
Colorectal cancer (CRC) is a complex disease characterized by genetic and epigenetic alterations, playing a crucial role in its development and progression. This review aims to provide insights into the emerging landscape of these alterations in CRC pathogenesis to develop effective diagnostic tools and targeted therapies. Genetic alterations in signaling pathways such as Wnt/β-catenin, and PI3K/Akt/mTOR are pivotal in CRC development. Genetic profiling has identified distinct molecular subtypes, enabling personalized treatment strategies. Epigenetic modifications, including DNA methylation and histone modifications, also contribute to CRC pathogenesis by influencing critical cellular processes through gene silencing or activation. Non-coding RNAs have emerged as essential players in epigenetic regulation and CRC progression. Recent research highlights the interplay between genetic and epigenetic alterations in CRC. Genetic mutations can affect epigenetic modifications, leading to dysregulated gene expression and signaling cascades. Conversely, epigenetic changes can modulate genetic expression, amplifying or dampening the effects of genetic alterations. Advancements in understanding pathogenic pathways have potential clinical applications. Identifying genetic and epigenetic markers as diagnostic and prognostic biomarkers promises more accurate risk assessment and early detection. Challenges remain, including validating biomarkers and developing robust therapeutic strategies through extensive research and clinical trials. The dynamic nature of genetic and epigenetic alterations necessitates a comprehensive understanding of their temporal and spatial patterns during CRC progression. In conclusion, the genetic and epigenetic landscape of CRC is increasingly being unraveled, providing valuable insights into its pathogenesis. Integrating genetic and epigenetic knowledge holds great potential for improving diagnostics, prognostics, and personalized therapies in CRC. Continued research efforts are vital to translate these findings into clinical practice, ultimately improving patient outcomes.
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Affiliation(s)
- Humzah Postwala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Yesha Shah
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India
| | - Priyajeet S Parekh
- AV Pharma LLC, 1545 University Blvd N Ste A, Jacksonville, Florida, 32211, USA
| | - Mehul R Chorawala
- Department of Pharmacology and Pharmacy Practice, L. M. College of Pharmacy, Opp. Gujarat University, Ahmedabad, 380009, Gujarat, India.
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Marx O, Mankarious M, Yochum G. Molecular genetics of early-onset colorectal cancer. World J Biol Chem 2023; 14:13-27. [PMID: 37034132 PMCID: PMC10080548 DOI: 10.4331/wjbc.v14.i2.13] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/20/2022] [Accepted: 02/13/2023] [Indexed: 03/24/2023] Open
Abstract
Early-onset colorectal cancer (EOCRC) has been rising in global prevalence and incidence over the past several decades. Environmental influences, including generational lifestyle changes and rising obesity, contribute to these increased rates. While the rise in EOCRC is best documented in western countries, it is seen throughout the world, although EOCRC may have distinct genetic mutations in patients of different ethnic backgrounds. Pathological and molecular characterizations show that EOCRC has a distinct presentation compared with later-onset colorectal cancer (LOCRC). Recent studies have identified DNA, RNA, and protein-level alterations unique to EOCRC, revealing much-needed biomarkers and potential novel therapeutic targets. Many molecular EOCRC studies have been performed with Caucasian and Asian EOCRC cohorts, however, studies of other ethnic backgrounds are limited. In addition, certain molecular characterizations that have been conducted for LOCRC have not yet been repeated in EOCRC, including high-throughput analyses of histone modifications, mRNA splicing, and proteomics on large cohorts. We propose that the complex relationship between cancer and aging should be considered when studying the molecular underpinnings of EOCRC. In this review, we summarize current EOCRC literature, focusing on sporadic molecular alterations in tumors, and their clinical implications. We conclude by discussing current challenges and future directions of EOCRC research efforts.
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Affiliation(s)
- Olivia Marx
- Department of Biochemistry & Molecular Biology, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
| | - Marc Mankarious
- Department of Surgery, Division of Colon & Rectal Surgery, Pennsylvania State University Milton S. Hershey Medical Center, Hershey, PA 17033, United States
| | - Gregory Yochum
- Department of Biochemistry & Molecular Biology & Surgery, Pennsylvania State University College of Medicine, Hershey, PA 17033, United States
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Zhang Y, Zhang L, Sun H, Liu Y, Xu J, Huang H, Fu J, Zhang D, Tian T, Zhao Y, Wang G. Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer. Mol Med 2021; 27:114. [PMID: 34544358 PMCID: PMC8454079 DOI: 10.1186/s10020-021-00373-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 09/05/2021] [Indexed: 12/24/2022] Open
Abstract
Background Changes in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk. Methods GSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case–control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk. Results In the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197–0.528; ORadj = 0.666, 95% CI 0.446–0.5996, respectively). Moreover, the results in case–control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322–0.622; ORadj = 0.417, 95% CI 0.301–0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk. Conclusions PDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk. Supplementary Information The online version contains supplementary material available at 10.1186/s10020-021-00373-5.
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Affiliation(s)
- Yuanyuan Zhang
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Ying Liu
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Jinming Fu
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Ding Zhang
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China
| | - Tian Tian
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China.
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College of Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang, People's Republic of China.
| | - Guiyu Wang
- Department of Colorectal Cancer Surgery, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Street, Nangang District, Harbin, 150001, Heilongjiang, People's Republic of China.
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Pham DAT, Le SD, Doan TM, Luu PT, Nguyen UQ, Ho SV, Vo LTT. Standardization of DNA amount for bisulfite conversion for analyzing the methylation status of LINE-1 in lung cancer. PLoS One 2021; 16:e0256254. [PMID: 34403448 PMCID: PMC8370637 DOI: 10.1371/journal.pone.0256254] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/04/2021] [Indexed: 11/18/2022] Open
Abstract
Highly methylated Long Interspersed Nucleotide Elements 1 (LINE-1) constitute approximately 20% of the human genome, thus serving as a surrogate marker of global genomic DNA methylation. To date, there is still lacking a consensus about the precise location in LINE-1 promoter and its methylation threshold value, making challenging the use of LINE-1 methylation as a diagnostic, prognostic markers in cancer. This study reports on a technical standardization of bisulfite-based DNA methylation analysis, which ensures the complete bisulfite conversion of repeated LINE-1 sequences, thus allowing accurate LINE-1 methylation value. In addition, the study also indicated the precise location in LINE-1 promoter of which significant variance in methylation level makes LINE-1 methylation as a potential diagnostic biomarker for lung cancer. A serial concentration of 5-50-500 ng of DNA from 275 formalin-fixed paraffin-embedded lung tissues were converted by bisulfite; methylation level of two local regions (at nucleotide position 300–368 as LINE-1.1 and 368–460 as LINE-1.2) in LINE-1 promoter was measured by real time PCR. The use of 5 ng of genomic DNA but no more allowed to detect LINE-1 hypomethylation in lung cancer tissue (14.34% versus 16.69% in non-cancerous lung diseases for LINE-1.1, p < 0.0001, and 30.28% versus 32.35% for LINE-1.2, p < 0.05). Our study thus highlighted the optimal and primordial concentration less than 5 ng of genomic DNA guarantees the complete LINE-1 bisulfite conversion, and significant variance in methylation level of the LINE-1 sequence position from 300 to 368 allowed to discriminate lung cancer from non-cancer samples.
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Affiliation(s)
| | - Son Duc Le
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Trang Mai Doan
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Phuong Thu Luu
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
| | - Uyen Quynh Nguyen
- Department of Biology, VNU Institute of Microbiology and Biotechnology, Hanoi, Vietnam
| | - Son Van Ho
- Department of Biochemistry, 175 Hospital, Ho Chi Minh City, Vietnam
| | - Lan Thi Thuong Vo
- Faculty of Biology, University of Science, Vietnam National University, Hanoi, Vietnam
- * E-mail:
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Done JZ, Fang SH. Young-onset colorectal cancer: A review. World J Gastrointest Oncol 2021; 13:856-866. [PMID: 34457191 PMCID: PMC8371519 DOI: 10.4251/wjgo.v13.i8.856] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2021] [Revised: 04/30/2021] [Accepted: 07/19/2021] [Indexed: 02/06/2023] Open
Abstract
Despite the general decrease in overall incidence of colorectal cancer since the early 1990s, the incidence of colorectal cancer in patients less than 50 years old has nearly doubled. A systematic review was performed using the PubMed database (2011-2020) and Cochrane Database of Systematic Reviews (2011-2021) to identify studies (published in English) evaluating epidemiologic, clinical, hereditary, and molecular features; as well as evaluation, management, and prognosis of young-onset colorectal cancer patients. Our search yielded a total of 3401 articles, after applying our inclusion criteria. We fully reviewed 94 full-length studies. This systematic review demonstrates the increasing incidence of young-onset colorectal cancer and highlights the importance of being hypervigilant for the differential diagnosis colorectal cancer when evaluating a young adult who presents with gastrointestinal symptoms.
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Affiliation(s)
- Joy Zhou Done
- Department of Surgery, Johns Hopkins Hospital, Baltimore, MD 21287, United States
| | - Sandy H Fang
- Department of Surgery, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, MD 21287, United States
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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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Joo JE, Clendenning M, Wong EM, Rosty C, Mahmood K, Georgeson P, Winship IM, Preston SG, Win AK, Dugué PA, Jayasekara H, English D, Macrae FA, Hopper JL, Jenkins MA, Milne RL, Giles GG, Southey MC, Buchanan DD. DNA Methylation Signatures and the Contribution of Age-Associated Methylomic Drift to Carcinogenesis in Early-Onset Colorectal Cancer. Cancers (Basel) 2021; 13:cancers13112589. [PMID: 34070516 PMCID: PMC8199056 DOI: 10.3390/cancers13112589] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/14/2021] [Accepted: 05/19/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The role of DNA methylation in the carcinogenesis of colorectal cancer (CRC) diagnosed <50 years of age (early-onset CRC or EOCRC) is currently unknown. In this study, we investigated the genome-wide DNA methylation of 97 tumour and 54 normal colonic mucosa samples from people with EOCRC with the aim of identifying unique DNA methylation signatures and determining the role of ageing-related DNA methylation drift and age-acceleration in EOCRC aetiology. We found extensive DNA methylation alterations associated with EOCRC carcinogenesis, including a unique signature comprising 234 loci compared with CRCs from people >50 years of age. CpGs that undergo ageing-related methylation drift were significantly altered in EOCRC, and accelerated ageing was also evident in normal mucosa from people with EOCRC. Our study is the first study to identify unique DNA methylation changes in EOCRC, contributing novel information that may aid future efforts towards EOCRC prevention. Abstract We investigated aberrant DNA methylation (DNAm) changes and the contribution of ageing-associated methylomic drift and age acceleration to early-onset colorectal cancer (EOCRC) carcinogenesis. Genome-wide DNAm profiling using the Infinium HM450K on 97 EOCRC tumour and 54 normal colonic mucosa samples was compared with: (1) intermediate-onset CRC (IOCRC; diagnosed between 50–70 years; 343 tumour and 35 normal); and (2) late-onset CRC (LOCRC; >70 years; 318 tumour and 40 normal). CpGs associated with age-related methylation drift were identified using a public dataset of 231 normal mucosa samples from people without CRC. DNAm-age was estimated using epiTOC2. Common to all three age-of-onset groups, 88,385 (20% of all CpGs) CpGs were differentially methylated between tumour and normal mucosa. We identified 234 differentially methylated genes that were unique to the EOCRC group; 13 of these DMRs/genes were replicated in EOCRC compared with LOCRCs from TCGA. In normal mucosa from people without CRC, we identified 28,154 CpGs that undergo ageing-related DNAm drift, and of those, 65% were aberrantly methylated in EOCRC tumours. Based on the mitotic-based DNAm clock epiTOC2, we identified age acceleration in normal mucosa of people with EOCRC compared with normal mucosa from the IOCRC, LOCRC groups (p = 3.7 × 10−16) and young people without CRC (p = 5.8 × 10−6). EOCRC acquires unique DNAm alterations at 234 loci. CpGs associated with ageing-associated drift were widely affected in EOCRC without needing the decades-long accrual of DNAm drift as commonly seen in intermediate- and late-onset CRCs. Accelerated ageing in normal mucosa from people with EOCRC potentially underlies the earlier age of diagnosis in CRC carcinogenesis.
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Affiliation(s)
- Jihoon E. Joo
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Mark Clendenning
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Ee Ming Wong
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
| | - Christophe Rosty
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- School of Medicine, University of Queensland, Herston, Brisbane 4006, Australia
- Envoi Pathology, Brisbane 4059, Australia
| | - Khalid Mahmood
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Melbourne Bioinformatics, The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Peter Georgeson
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Ingrid M. Winship
- Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne 3050, Australia; (I.M.W.); (F.A.M.)
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
| | - Susan G. Preston
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Pierre-Antoine Dugué
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Harindra Jayasekara
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Dallas English
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Finlay A. Macrae
- Department of Medicine, The Royal Melbourne Hospital, University of Melbourne, Parkville, Melbourne 3050, Australia; (I.M.W.); (F.A.M.)
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
| | - John L. Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Mark A. Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
| | - Roger L. Milne
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Graham G. Giles
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Melbourne 3010, Australia; (A.K.W.); (D.E.); (J.L.H.); (M.A.J.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
| | - Melissa C. Southey
- Precision Medicine, Monash Health, Monash University, Clayton, Melbourne 3800, Australia; (E.M.W.); (P.-A.D.); (R.L.M.); (G.G.G.); (M.C.S.)
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne 3004, Australia
- Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia
| | - Daniel D. Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Melbourne 3010, Australia; (J.E.J.); (M.C.); (C.R.); (K.M.); (P.G.); (S.G.P.); (H.J.)
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Melbourne 3000, Australia
- Genomic Medicine and Family Cancer Clinic, Royal Melbourne Hospital, Parkville, Melbourne 3050, Australia
- Correspondence: ; Tel.: +61-3-8559-7004
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Onwuka JU, Li D, Liu Y, Huang H, Xu J, Liu Y, Zhang Y, Zhao Y. A panel of DNA methylation signature from peripheral blood may predict colorectal cancer susceptibility. BMC Cancer 2020; 20:692. [PMID: 32711505 PMCID: PMC7382833 DOI: 10.1186/s12885-020-07194-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Accepted: 07/19/2020] [Indexed: 02/07/2023] Open
Abstract
Background Differential DNA methylation panel derived from peripheral blood could serve as biomarkers of CRC susceptibility. However, most of the previous studies utilized post-diagnostic blood DNA which may be markers of disease rather than susceptibility. In addition, only a few studies have evaluated the predictive potential of differential DNA methylation in CRC in a prospective cohort and on a genome-wide basis. The aim of this study was to identify a potential panel of DNA methylation biomarkers in peripheral blood that is associated with CRC risk and therefore serve as epigenetic biomarkers of disease susceptibility. Methods DNA methylation profile of a nested case-control study with 166 CRC and 424 healthy normal subjects were obtained from the Gene Expression Omnibus (GEO) database. The differentially methylated markers were identified by moderated t-statistics. The DNA methylation panel was constructed by stepwise logistic regression and the least absolute shrinkage and selection operator in the training dataset. A methylation risk score (MRS) model was constructed and the association between MRS and CRC risk assessed. Results We identified 48 differentially methylated CpGs sites, of which 33 were hypomethylated. Of these, sixteen-CpG based MRS that was associated with CRC risk (OR = 2.68, 95% CI: 2.13, 3.38, P < 0.0001) was constructed. This association is confirmed in the testing dataset (OR = 2.02, 95% CI: 1.48, 2.74, P < 0.0001) and persisted in both males and females, younger and older subjects, short and long time-to-diagnosis. The MRS also predicted CRC with AUC 0.82 (95% CI: 0.76, 0.88), indicating high accuracy. Conclusions Our study has identified a novel DNA methylation panel that is associated with CRC and could, if validated be useful for the prediction of CRC risk in the future.
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Affiliation(s)
- Justina Ucheojor Onwuka
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Dapeng Li
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Ying Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China.
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Ma LY, Zhang N, Liu JT, Zhai XY, Lv Y, Lu FF, Yang H. Uptake of atrazine in a paddy crop activates an epigenetic mechanism for degrading the pesticide in plants and environment. ENVIRONMENT INTERNATIONAL 2019; 131:105014. [PMID: 31351384 DOI: 10.1016/j.envint.2019.105014] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2019] [Revised: 06/15/2019] [Accepted: 07/11/2019] [Indexed: 06/10/2023]
Abstract
There is a rising public concern on accumulation of harmful pesticides in environment and crops. Epigenetic alteration caused by environmental contaminants is one of the key factors in the etiology of environmentally-associated diseases. Growing evidence shows that harmful pesticide atrazine (ATZ) has a profound effect on DNA methylation in human genome, however, little is known about the epigenetic mechanism underlying ATZ accumulation and degradation in plants, particularly in edible plants growing in the ATZ-contaminated areas. This study investigated the atrazine elimination that was mediated by DNA methylation and histone modification in the food crop rice. Studies with two mutant Osmet1-1/2 defective in the genomic CG DNA methylation show significantly lower accumulation of atrazine than its wild-types. Profiling methylome and transcriptome of ATZ-exposed Osmet1 and wild-type identified many differentially methylated loci (≥2 fold change, p < 0.05), which were associated with activation of genes responsible for atrazine degradation in plants. Three demethylated loci OsGTF, OsHPL1 and OsGLH were expressed in eukaryotic yeast cells and found to eliminate a marked proportion of ATZ in growth environments by 48%, 43% and 32%, respectively, whereas the increased ATZ-degraded products were characterized using UPLC/Q-TOF-MS/MS. These results suggest that activation of the loci mediated by ATZ-induced hypomethylation could be responsible for the removal of ATZ in rice. Our work helps understand a new regulatory mechanism underlying the atrazine degradation in crops which may potentially reduce the environmental risks to human health through food chain.
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Affiliation(s)
- Li Ya Ma
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Nan Zhang
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Jin Tong Liu
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Xiao Yan Zhai
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Yun Lv
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Feng Fan Lu
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China
| | - Hong Yang
- Jiangsu Key Laboratory of Pesticide Science, College of Sciences, Nanjing Agricultural University, Nanjing 210095, China; State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Nanjing Agricultural University, Nanjing 210095, China.
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Bi H, Liu Y, Pu R, Xia T, Sun H, Huang H, Zhang L, Zhang Y, Liu Y, Xu J, Rong J, Zhao Y. CHST7 Gene Methylation and Sex-Specific Effects on Colorectal Cancer Risk. Dig Dis Sci 2019; 64:2158-2166. [PMID: 30815821 DOI: 10.1007/s10620-019-05530-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 02/11/2019] [Indexed: 01/09/2023]
Abstract
BACKGROUND X chromosome aberrations are involved in carcinogenesis and are associated with gender differences in cancer development. Abnormal DNA methylation also contributes to cancer. Carbohydrate Sulfotransferase 7 (CHST7), encoded by the X chromosome, is abnormally expressed during tumor development. However, its impact on colorectal cancer (CRC) and the effect of CHST7 methylation on sex-specific CRC risk remain unclear. AIMS To investigate the effect of CHST7 methylation in white blood cells on CRC risk and to evaluate its impact on gender-specific differences. METHODS CHST7 methylation in white blood cells was determined using methylation-sensitive high-resolution melting. A propensity score analysis was performed to control potential confounders. Furthermore, extensive sensitivity analyses were applied to assess the robustness of our findings. In addition, we validated the initial findings with a GEO dataset (GSE51032). RESULTS CHST7 hypermethylation in white blood cells was associated with an increased CRC risk [odds ratio (OR)adj = 4.447, 95% confidence interval (CI) 2.662-7.430; p < 0.001]. The association was validated with the GEO dataset (ORadj = 2.802, 95% CI 1.235-6.360; p = 0.014). In particular, CHST7 hypermethylation significantly increased the CRC risk in females (ORadj = 7.704, 95% CI 4.222-14.058; p < 0.001) and younger patients (≤ 60 years) (ORadj = 5.755, 95% CI 2.540-13.038; p < 0.001). Subgroup analyses by tumor location and Duke's stage also observed these associations. CONCLUSION CHST7 methylation in white blood cells is positively associated with CRC risk, especially in females, and may potentially serve as a blood-based predictive biomarker for CRC risk.
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Affiliation(s)
- Haoran Bi
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Rui Pu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Tingting Xia
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Hao Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Lei Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yuanyuan Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Ying Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Jing Xu
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Jiesheng Rong
- Department of Orthopedics Surgery, The Second Affiliated Hospital of Harbin Medical University, 246, Xuefu Street, Harbin, 150081, Heilongjiang Province, People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, 157 Baojian Street, Nangang District, Harbin, 150081, Heilongjiang Province, People's Republic of China.
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Lv Y, Zheng X, Shi M, Wang Z, Cui L. Different EPHX1 methylation levels in promoter area between carbamazepine-resistant epilepsy group and carbamazepine-sensitive epilepsy group in Chinese population. BMC Neurol 2019; 19:114. [PMID: 31164100 PMCID: PMC6549255 DOI: 10.1186/s12883-019-1308-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 04/18/2019] [Indexed: 12/13/2022] Open
Abstract
Background Epigenetics underlying refractory epilepsy is poorly understood. DNA methylation may affect gene expression in epilepsy patients without affecting DNA sequences. Herein, we investigated the association between Carbamazepine-resistant (CBZ-resistant) epilepsy and EPHX1 methylation in a northern Han Chinese population, and conducted an analysis of clinical risk factors for CBZ-resistant epilepsy. Methods Seventy-five northern Han Chinese patients participated in this research. 25 cases were CBZ-resistant epilepsy, 25 cases were CBZ-sensitive epilepsy and the remaining 25 cases were controls. Using a CpG searcher was to make a prediction of CpG islands; bisulfite sequencing PCR (BSP) was applied to test the methylation of EPHX1. We then did statistical analysis between clinical parameters and EPHX1 methylation. Results There was no difference between CBZ-resistant patients, CBZ-sensitive patients and healthy controls in matched age and gender. However, a significant difference of methylation levels located in NC_000001.11 (225,806,929.....225807108) of the EPHX1 promoter was found in CBZ-resistant patients, which was much higher than CBZ-sensitive and controls. Additionally, there was a significant positive correlation between seizure frequency, disease course and EPHX1 methylation in CBZ-resistant group. Conclusion Methylation levels in EPHX1 promoter associated with CBZ-resistant epilepsy significantly. EPHX1 methylation may be the potential marker for CBZ resistance prior to the CBZ therapy and potential target for treatments.
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Affiliation(s)
- Yudan Lv
- Department of Neurology, The First hospital of Jilin University, 71-Xinmin Street, Changchun, People's Republic of China
| | - Xiangyu Zheng
- Department of Neurology, The First hospital of Jilin University, 71-Xinmin Street, Changchun, People's Republic of China
| | - Mingchao Shi
- Department of Neurology, The First hospital of Jilin University, 71-Xinmin Street, Changchun, People's Republic of China
| | - Zan Wang
- Department of Neurology, The First hospital of Jilin University, 71-Xinmin Street, Changchun, People's Republic of China
| | - Li Cui
- Department of Neurology, The First hospital of Jilin University, 71-Xinmin Street, Changchun, People's Republic of China.
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Woraruthai T, Charoenlap C, Hongsaprabhas C, Mutirangura A, Honsawek S. Alu hypermethylation and high oxidative stress in patients with musculoskeletal tumors. PeerJ 2018; 6:e5492. [PMID: 30128216 PMCID: PMC6098941 DOI: 10.7717/peerj.5492] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Accepted: 07/27/2018] [Indexed: 01/13/2023] Open
Abstract
Background Alu is one of the non-autonomous element retrotransposons, constituting nearly 11% of the human DNA. Methylation changes of the Alu element can cause genomic instability, a hallmark of cancer development, ultimately leading to the development of cancer. Epigenetic factors may induce the aberrant methylation of Alu and also oxidative stress. However, current knowledge of Alu methylation and oxidative stress is limited. There are few studies that have evaluated Alu methylation and oxidative stress on musculoskeletal tumor progression. Therefore, the present study evaluated the status of Alu methylation in musculoskeletal (MS) tumor, adjacent tissues, and blood leukocytes from MS tumor subjects, as well as unaffected participants. Moreover, we also investigated the oxidative stress status in MS tumor subjects and the control participants and determined the correlation between Alu methylation in MS tumors and that in blood leukocytes. Methods Musculoskeletal tumors from musculoskeletal tumor patients (n = 40) were compared to adjacent tissues (n = 40). The blood leukocytes from musculoskeletal tumor patients were compared to the blood leukocytes from controls (n = 107). Alu methylation status was analyzed using quantitative combined bisulfite restriction analysis (COBRA). In addition, 8-hydroxy 2'-deoxyguanosine (8-OHdG) values were determined using enzyme-linked immunosorbent assay. Results Alu methylation values in MS tumors were statistically significantly higher than those in adjacent tissues (P = 0.035). Similarly, Alu methylation statuses in the blood leukocytes of MS tumor subjects were statistically greater than those of control participants (P < 0.001). Moreover, there was a positive association between Alu methylation levels in MS tumors and blood leukocytes (r = 0.765, P < 0.001). In addition, the highest tertile was significantly associated with the risk of MS tumors (OR = 14.17, 95% CI [5.08-39.51]; P < 0.001). The 8-OHdG values in MS tumors were statistically higher than in adjacent tissues (P < 0.001) and circulating 8-OHdG levels were substantially greater in MS tumor subjects than in the control participants (P < 0.001). Discussion These findings suggest that Alu methylation in blood leukocytes and plasma 8-OHdG might represent non-invasive biomarkers to help diagnose MS tumors. Therefore, Alu hypermethylation and high oxidative stress might be involved in the pathogenesis of the musculoskeletal tumors.
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Affiliation(s)
- Thamonwan Woraruthai
- Osteoarthritis and Musculoskeleton Research Unit, Department of Biochemistry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Chris Charoenlap
- Department of Orthopaedics, Vinai Parkpian Orthopaedic Research Center, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Chindanai Hongsaprabhas
- Department of Orthopaedics, Vinai Parkpian Orthopaedic Research Center, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Apiwat Mutirangura
- Center for Excellence in Molecular Genetics of Cancer & Human Diseases, Department of Anatomy, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
| | - Sittisak Honsawek
- Osteoarthritis and Musculoskeleton Research Unit, Department of Biochemistry, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Chulalongkorn University, Bangkok, Thailand
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Lu S, Niu Z, Chen Y, Tu Q, Zhang Y, Chen W, Tong W, Zhang Z. Repetitive Element DNA Methylation is Associated with Menopausal Age. Aging Dis 2018; 9:435-443. [PMID: 29896431 PMCID: PMC5988598 DOI: 10.14336/ad.2017.0810] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 08/10/2017] [Indexed: 12/21/2022] Open
Abstract
To investigate associations between the age of menopause and the DNA methylation levels of two repetitive elements, Alu and LINE-1, we performed plasma DNA extraction on 161 subjects and serum cell-free DNA extraction on 120 subjects. We grouped women by menopausal age as follows: ≤ 48 years (earlier menopause), ≥ 52 years (later menopause), and 48-52 years (control). The DNA methylation levels of Alu and LINE-1 were measured by MethyLight PCR. The results showed that the DNA methylation levels of both Alu and LINE-1 were inversely correlated with menopausal age in the plasma DNA cohort (r = 0.079, P < 0.001 for Alu; r = 0.045, P = 0.007 for LINE-1) as well as in the serum DNA cohort (r = 0.087, P = 0.001 for Alu; r = 0.041, P = 0.026 for LINE-1). Alu methylation levels in both the plasma and serum DNA cohorts and LINE-1 methylation levels in the plasma cohort were remarkably higher in the earlier menopause group than in the later menopause and control groups (P < 0.01 and P < 0.05, respectively). In the serum DNA cohort, the LINE-1 methylation levels in the later menopause group were significantly lower than that in the earlier menopause group and control group (P < 0.05). Therefore, methylation levels of Alu and LINE-1 were significantly associated with menopausal age. Women with earlier menopause showed hypermethylation in both repetitive elements, while women with later menopause showed hypomethylation. These findings suggest that altered DNA methylation in leukocytes and serum cell-free DNA may represent a biomarker of menopausal age.
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Affiliation(s)
- Sha Lu
- 1Department of Obstetrics and Gynecology, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China.,2Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Zheng Niu
- 1Department of Obstetrics and Gynecology, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China
| | - Yueming Chen
- 3Laboratory of Gene Diagnosis, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China
| | - Qiaofeng Tu
- 3Laboratory of Gene Diagnosis, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China
| | - Yue Zhang
- 2Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
| | - Wenli Chen
- 4Department of Obstetrics and Gynecology, the Second People's Hospital of Tonglu, Hangzhou, China
| | - Wenjuan Tong
- 3Laboratory of Gene Diagnosis, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China
| | - Zhifen Zhang
- 1Department of Obstetrics and Gynecology, the Affiliated Hangzhou People's Hospital of Nanjing Medical University, Hangzhou, China.,2Department of Obstetrics and Gynecology, Hangzhou Women's Hospital (Hangzhou Maternity and Child Health Care Hospital), Hangzhou, China
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Cheng L, Shen Z, Zhou C. Promoter hypermethylation of PIEZO2 is a risk factor and potential clinical biomarker for laryngeal squamous cell carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:11635-11643. [PMID: 31966521 PMCID: PMC6966076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/22/2017] [Indexed: 06/10/2023]
Abstract
The aim of this study was to investigate the association between piezo type mechanosensitive ion channel component 2 (PIEZO2)-promoter methylation with and its clinical value for laryngeal squamous cell carcinoma (LSCC). Quantitative methylation-specific polymerase chain reaction technology was applied to measure PIEZO2 promoter methylation levels from 99 LSCC patients. Inclusive in the analysis were 133 (117 LSSC and 16 normal) samples from The Cancer Genome Atlas (TCGA). Our results showed significantly higher levels of PIEZO2 promoter methylation in LSCC than normal tissues (our cohort: P = 2.94E-21; TCGA cohort: P = 1.07E-19). In addition, PIEZO2 methylation was significantly associated with gender, differentiation, tumor (T) stage, lymph node metastasis, and clinical stage. The areas under the receiver characteristic curves (AUCs) based on our cohort and TCGA cohort were 0.917 and 0.978, respectively. Meanwhile, our study confirmed that PIEZO2 promoter hypermethylation could independently predict a poorer overall survival of LSCC patients (hazard ratio = 6.671; 95% confidence interval = 2.087-21.324). In conclusion, our study revealed that PIEZO2 promoter hypermethylation was a risk factor and might be involved in progression and metastasis, as well as serve as a potential clinical biomarker of LSCC.
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Affiliation(s)
- Lixin Cheng
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University Ningbo, Zhejiang, China
| | - Zhisen Shen
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University Ningbo, Zhejiang, China
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University Ningbo, Zhejiang, China
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Li J, Zhou C, Wang G, Wang S, Ni S, Ye M, Zhang J. Promoter hypermethylation of SLIT2 is a risk factor and potential diagnostic biomarker for nasopharyngeal carcinoma. Gene 2017; 644:74-79. [PMID: 29107007 DOI: 10.1016/j.gene.2017.10.059] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Revised: 10/04/2017] [Accepted: 10/20/2017] [Indexed: 02/06/2023]
Abstract
SLIT2 is a candidate tumor suppressor gene and recent studies have shown that SLIT2 expression is suppressed or reduced by hypermethylation in the promoter region in various cancers. The aim of this study was to investigate the association between SLIT2 promoter methylation and nasopharyngeal carcinoma (NPC) and its relative diagnostic ability for NPC. Bisulfite pyrosequencing technology was performed to measure methylation levels of the SLIT2 promoter in tissue and plasma samples from 61 NPC patients and 38 normal volunteers. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic ability of SLIT2 methylation for diagnosing NPC. Our results showed that methylation levels of the SLIT2 promoter were significantly higher in NPC patients compared with individuals, both in tissue samples (P=2.57E-10) and plasma samples (plasma: P=3.86E-13). In addition, the frequency of SLIT2 promoter methylation markedly increased in the advanced stage (tissue: P=3.50E-05; plasma: P=1.14E-04) and advanced T classified (tissue: P=9.00E-06; plasma: P=3.80E-05), as well as in lymph node metastasis patients (tissue: P=1.82E-03; plasma: P=2.22E-03). In addition, the AUCs according to tissue and plasma samples were 0.846 and 0.866, respectively. When these two sample-types were combined, the AUC increased slightly to 0.874. Our study revealed that elevated SLIT2 promoter methylation contributed to the risk of NPC, as well as being involved in its progression and metastasis. Therefore, the methylated SLIT2 promoter could serve as a potential biomarker for diagnosing NPC.
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Affiliation(s)
- Jinyun Li
- Department of Oncology and Hematology, Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang, China
| | - Chongchang Zhou
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo 315040, Zhejiang, China.
| | - Guoli Wang
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo 315040, Zhejiang, China
| | - Shaomin Wang
- Department of Oncology and Hematology, Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang, China
| | - Shuming Ni
- Department of Oncology and Hematology, Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang, China
| | - Meng Ye
- Department of Oncology and Hematology, Affiliated Hospital of Ningbo University, Ningbo 315000, Zhejiang, China.
| | - Jian Zhang
- Department of Otorhinolaryngology Head and Neck Surgery, Lihuili Hospital of Ningbo University, Ningbo 315040, Zhejiang, China.
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Barchitta M, Quattrocchi A, Maugeri A, Canto C, La Rosa N, Cantarella MA, Spampinato G, Scalisi A, Agodi A. LINE-1 hypermethylation in white blood cell DNA is associated with high-grade cervical intraepithelial neoplasia. BMC Cancer 2017; 17:601. [PMID: 28854904 PMCID: PMC5577847 DOI: 10.1186/s12885-017-3582-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Accepted: 08/22/2017] [Indexed: 12/23/2022] Open
Abstract
Background Long Interspersed Nuclear Elements-1 (LINEs-1) methylation from white blood cells (WBCs) DNA has been proposed as biomarker associated with different types of cancer. The aim of the present study was to investigate the degree of WBCs LINE-1 methylation, according to high-risk Human Papilloma Virus (hrHPV) status in a healthy population, and the association with high-grade Cervical Intraepithelial Neoplasia (CIN2+) in hrHPV positive women. Methods Women with abnormal cervical cells were enrolled and classified by histological diagnosis and hrHPV infection. A structured questionnaire was used to obtain information on socio-demographic variables and lifestyle factors. LINE-1 methylation level in WBCs was measured by pyrosequencing-based methylation analysis after bisulfite conversion. Results Among 252 women diagnosed with normal cervical epithelium, with regard to LINE-1 methylation level no significant difference was observed between hrHPV positive and hrHPV negative women, also adjusting for known risk factors of infection. The association between WBCs LINE-1 methylation and CIN2+ status was analyzed in hrHPV positive women. The median value of LINE-1 methylation levels was higher in cases (CIN2+) than in controls (75.00% versus 73.17%; p = 0.002). For a one-unit increase in LINE-1 methylation level, the odds of being diagnosed with CIN2+ increased by 10%, adjusting for known factors related to LINE-1 methylation (adjOR: 1.10; 95% CI:1.01–1.20; p = 0.032). The Receiver-Operating Characteristic (ROC) curve analysis identified the cut-off value of 73.8% as the best threshold to separate cases from controls (sensitivity: 63.4% and specificity: 61.8%). Conclusions LINE-1 methylation status in WBCs DNA may represent a cost-effective and tissue-accessible biomarker for high-grade CIN in hrHPV positive women. However, LINE-1 hypermethylation cannot be considered specific for cervical cancer (CC) and a model based solely on LINE-1 methylation levels has limited performance. Further investigations are necessary to propose and validate a novel methylation biomarker panel, based on LINE-1 methylation and other differentially methylated regions, for the screening of women at risk of CC.
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Affiliation(s)
- Martina Barchitta
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, via S. Sofia, 87, 95121, Catania, Italy
| | - Annalisa Quattrocchi
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, via S. Sofia, 87, 95121, Catania, Italy
| | - Andrea Maugeri
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, via S. Sofia, 87, 95121, Catania, Italy
| | | | - Nadia La Rosa
- Unità Operativa di Screening Ginecologico, Azienda Sanitaria Provinciale 3, Catania, Italy
| | | | - Giuseppa Spampinato
- Unità Operativa di Screening Ginecologico, Azienda Sanitaria Provinciale 3, Catania, Italy
| | - Aurora Scalisi
- Unità Operativa di Screening Ginecologico, Azienda Sanitaria Provinciale 3, Catania, Italy
| | - Antonella Agodi
- Department of Medical and Surgical Sciences and Advanced Technologies "GF Ingrassia", University of Catania, via S. Sofia, 87, 95121, Catania, Italy.
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18
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Pinto-Medel MJ, Oliver-Martos B, Urbaneja-Romero P, Hurtado-Guerrero I, Ortega-Pinazo J, Serrano-Castro P, Fernández Ó, Leyva L. Global methylation correlates with clinical status in multiple sclerosis patients in the first year of IFNbeta treatment. Sci Rep 2017; 7:8727. [PMID: 28821874 PMCID: PMC5562733 DOI: 10.1038/s41598-017-09301-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Accepted: 07/25/2017] [Indexed: 02/08/2023] Open
Abstract
The alteration of DNA methylation patterns are a key component of disease onset and/or progression. Our objective was to evaluate the differences in Long Interspersed Nuclear Element-1 (LINE-1) methylation levels, as a surrogate marker of global DNA methylation, between multiple sclerosis (MS) patients and healthy controls. In addition, we assessed the association of LINE-1 methylation with clinical disease activity in patients treated with IFNbeta (IFNβ). We found that individuals with high levels of LINE-1 methylation showed 6-fold increased risk of suffering MS. Additionally, treated MS patients who bear high LINE-1 methylation levels had an 11-fold increased risk of clinical activity. Moreover, a negative correlation between treatment duration and percentage of LINE-1 methylation, that was statistically significant exclusively in the group of patients without clinical activity, was observed. Our data suggest that in MS patients, a slight global DNA hypermethylation occurs that may be related to the pathophysiology of the disease. In addition, global DNA methylation levels could play a role as a biomarker for the differential clinical response to IFNβ.
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Affiliation(s)
- María Jesús Pinto-Medel
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain.
| | - Begoña Oliver-Martos
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain
| | - Patricia Urbaneja-Romero
- UGC Neurociencias, Servicio de Neurología, Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS), Málaga, Spain
| | - Isaac Hurtado-Guerrero
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain
| | - Jesús Ortega-Pinazo
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain
| | - Pedro Serrano-Castro
- UGC Neurociencias, Servicio de Neurología, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Óscar Fernández
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain
| | - Laura Leyva
- UGC Neurociencias, Laboratorio de Investigación. Instituto de Investigación Biomedica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga (UMA), Málaga, Spain
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19
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Danese E, Montagnana M. Epigenetics of colorectal cancer: emerging circulating diagnostic and prognostic biomarkers. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:279. [PMID: 28758105 DOI: 10.21037/atm.2017.04.45] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide and the second leading cause of cancer-related mortality in western countries. Despite the high incidence, treatment options for advanced CRC remain limited and unsuccessful, resulting in a poor prognosis. Therefore, novel accurate diagnostic, prognostic and predictive biomarkers are clearly and urgently needed to detect advanced colon polyps and early stage CRC and to identify the most effective treatments for specific CRC patients. CRC is known to develop from early premalignant lesions to full blown cancer via a multi-step process involving a series of genetic mutations that accumulate over time. Recent improvement of our understanding of CRC biology and advances in genomic technologies has led to the identification of a variety of epigenetic alterations strongly involved in cancer initiation and progression. Among the epigenetic marks implicated in CRC the most widely studied are the global DNA hypomethylation, the promoter hypermethylation and the miRNAs dysregulations. Many evidence exist that such tumour associated alterations may serve as new potential biomarkers. Moreover, due the non-invasive, objective, and potential reproducible assessment, circulating epigenetic biomarkers have reached increasing attentions in the last few years. In this review, we attempt to analyze the existing most recent literature on the role of circulating DNA methylations and miRNAs alterations in CRC diagnosis and prognosis.
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Affiliation(s)
- Elisa Danese
- Clinical Biochemistry Section, University Hospital of Verona, Verona, Italy
| | - Martina Montagnana
- Clinical Biochemistry Section, University Hospital of Verona, Verona, Italy
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20
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Qu XL, Ming-Zhang, Yuan-Fang, Wang H, Zhang YZ. Effect of 2,3',4,4',5-Pentachlorobiphenyl Exposure on Endometrial Receptivity and the Methylation of HOXA10. Reprod Sci 2017. [PMID: 28631552 DOI: 10.1177/1933719117711258] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Polychlorinated biphenyls (PCBs) are one of the most common endocrine-disrupting chemicals and have obvious toxicity on human reproductive development. The aim of our study was to investigate the toxicity of chronic 2,3',4,4',5-pentachlorobiphenyl (PCB 118) exposure on embryo implantation and endometrial receptivity, with the possible mechanism of DNA methylation involved. Virgin CD-1 female mice (3 weeks old) were housed and orally treated with PCB 118 (0, 1, 10, 100 μg/kg) for a month. After mating with fertile males, the pregnant mice were killed on gestation day 4.5. Compared with the control group, implantation failures were observed in 1 μg/kg PCB 118- and 100 μg/kg PCB 118-treated groups. Abnormal endometrial morphology with open uterine lumens and densely compact stromal cells and poorly developed pinopodes were substantially in response to PCB 118 doses above, as well as the significant downregulation of implantation-associated genes (estrogen receptor 1, homeobox A10 [HOXA10], integrin subunit beta 3) and hypermethylation in the promoter region of HOXA10 further. It was confirmed that chronic exposure to PCB 118 produced an increased number of implantation failures in association with a defective uterine morphology during the implantation period. Alterations in methylation of HOXA10 could explain, at least in part, the mechanism of effects of PCB 118 exposure on the implantation process.
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Affiliation(s)
- Xin-Lan Qu
- 1 The Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, China.,2 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,3 Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan, China
| | - Ming-Zhang
- 1 The Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, China.,2 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,3 Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan, China
| | - Yuan-Fang
- 4 Department of Oncology, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Hui Wang
- 3 Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan, China.,5 Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan, China
| | - Yuan-Zhen Zhang
- 1 The Reproductive Medicine Center, Zhongnan Hospital of Wuhan University, Wuhan, China.,2 Department of Obstetrics and Gynecology, Zhongnan Hospital of Wuhan University, Wuhan, China.,3 Hubei Provincial Key Laboratory of Developmentally Originated Diseases, Wuhan, China
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21
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Liu Y, Wang Y, Hu F, Sun H, Zhang Z, Wang X, Luo X, Zhu L, Huang R, Li Y, Li G, Li X, Lin S, Wang F, Liu Y, Rong J, Yuan H, Zhao Y. Multiple gene-specific DNA methylation in blood leukocytes and colorectal cancer risk: a case-control study in China. Oncotarget 2017; 8:61239-61252. [PMID: 28977860 PMCID: PMC5617420 DOI: 10.18632/oncotarget.18054] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 04/07/2017] [Indexed: 12/17/2022] Open
Abstract
The relationship between gene-specific DNA methylation in peripheral blood leukocytes and colorectal cancer (CRC) susceptibility is unclear. In this case-control study, the methylation status of a panel of 10 CRC-related genes in 428 CRC cases and 428 cancer-free controls were detected with methylation-sensitive high-resolution melting analysis. We calculated a weighted methylation risk score (MRS) that comprehensively combined the methylation status of the panel of 10 genes and found that the MRS_10 was significantly associated with CRC risk. Compared with MRS-Low group, MRS-High group and MRS-Medium group exhibited a 6.51-fold (95% CI, 3.77-11.27) and 3.85-fold (95% CI, 2.72-5.45) increased risk of CRC, respectively. Moreover, the CRC risk increased with increasing MRS_10 (Ptrend < 0.0001). Stratified analyses demonstrated that the significant association retained in both men and women, younger and older, and normal weight or underweight and overweight or obese subjects. The area under the receiver operating characteristic curves for the MRS_10 model was 69.04% (95% CI, 65.57-72.66%) and the combined EF and MRS_10 model yielded an AUC of 79.12% (95% CI, 76.22-82.15%). Together, the panel of 10 gene-specific DNA methylation in leukocytes was strongly associated with the risk of CRC and might be a useful marker of susceptibility for CRC.
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Affiliation(s)
- Yupeng Liu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Yibaina Wang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Fulan Hu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Hongru Sun
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Zuoming Zhang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Xuan Wang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Xiang Luo
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Lin Zhu
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Rong Huang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Yan Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Guangxiao Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Xia Li
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Shangqun Lin
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Fan Wang
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Yanhong Liu
- Department of Clinical Laboratory, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Jiesheng Rong
- Department of Orthopedics Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Huiping Yuan
- Key Laboratory of Ophthalmology, Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
| | - Yashuang Zhao
- Department of Epidemiology, Public Health College, Harbin Medical University, Harbin 150081, Heilongjiang Province, The People's Republic of China
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22
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Durso DF, Bacalini MG, Sala C, Pirazzini C, Marasco E, Bonafé M, do Valle ÍF, Gentilini D, Castellani G, Faria AMC, Franceschi C, Garagnani P, Nardini C. Acceleration of leukocytes' epigenetic age as an early tumor and sex-specific marker of breast and colorectal cancer. Oncotarget 2017; 8:23237-23245. [PMID: 28423572 PMCID: PMC5410300 DOI: 10.18632/oncotarget.15573] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 02/12/2017] [Indexed: 01/12/2023] Open
Abstract
Changes in blood epigenetic age have been associated with several pathological conditions and have recently been described to anticipate cancer development. In this work, we analyze a publicly available leukocytes methylation dataset to evaluate the relation between DNA methylation age and the prospective development of specific types of cancer. We calculated DNA methylation age acceleration using five state-of-the-art estimators (three multi-site: Horvath, Hannum, Weidner; and two CpG specific: ELOV2 and FHL2) in a cohort including 845 subjects from the EPIC-Italy project and we compared 424 samples that remained cancer-free over the approximately ten years of follow-up with 235 and 166 subjects who developed breast and colorectal cancer, respectively. We show that the epigenetic age estimated from blood DNA methylation data is statistically significantly associated to future breast and male colorectal cancer development. These results are corroborated by survival analysis that shows significant association between age acceleration and cancer incidence suggesting that the chance of developing age-related diseases may be predicted by circulating epigenetic markers, with a dependence upon tumor type, sex and age estimator. These are encouraging results towards the non-invasive and perspective usage of epigenetic biomarkers.
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Affiliation(s)
- Danielle Fernandes Durso
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- National Counsel of Technological and Scientific Development (CNPq), Ministry of Science Technology and Innovation (MCTI), Brasilia, Brazil
| | | | - Claudia Sala
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
- Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
| | - Chiara Pirazzini
- IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy
| | - Elena Marasco
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | - Massimiliano Bonafé
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy
| | | | - Davide Gentilini
- Istituto Auxologico Italiano IRCCS, Cusano Milanino, Milan, Italy
| | - Gastone Castellani
- Department of Physics and Astronomy, University of Bologna, Bologna, Italy
- Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
| | - Ana Maria Caetano Faria
- Biochemistry and Immunology Department, Biological Sciences Institute, Federal University of Minas Gerais, Belo Horizonte, Brazil
| | | | - Paolo Garagnani
- Department of Experimental, Diagnostic and Specialty Medicine, Alma Mater Studiorum-University of Bologna, Bologna, Italy
- Applied Biomedical Research Center, S. Orsola-Malpighi Polyclinic, Bologna, Italy
- Interdepartmental Center “L. Galvani”, University of Bologna, Bologna, Italy
- Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, Stockholm, Sweden
| | - Christine Nardini
- Personal Genomics S.r.l., Verona, Italy
- CNR IAC “Mauro Picone”, Rome, Italy
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23
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Reichetzeder C, Dwi Putra SE, Pfab T, Slowinski T, Neuber C, Kleuser B, Hocher B. Increased global placental DNA methylation levels are associated with gestational diabetes. Clin Epigenetics 2016; 8:82. [PMID: 27462376 PMCID: PMC4960714 DOI: 10.1186/s13148-016-0247-9] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2016] [Accepted: 07/11/2016] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Gestational diabetes mellitus (GDM) is associated with adverse pregnancy outcomes. It is known that GDM is associated with an altered placental function and changes in placental gene regulation. More recent studies demonstrated an involvement of epigenetic mechanisms. So far, the focus regarding placental epigenetic changes in GDM was set on gene-specific DNA methylation analyses. Studies that robustly investigated placental global DNA methylation are lacking. However, several studies showed that tissue-specific alterations in global DNA methylation are independently associated with type 2 diabetes. Thus, the aim of this study was to characterize global placental DNA methylation by robustly measuring placental DNA 5-methylcytosine (5mC) content and to examine whether differences in placental global DNA methylation are associated with GDM. METHODS Global DNA methylation was quantified by the current gold standard method, LC-MS/MS. In total, 1030 placental samples were analyzed in this single-center birth cohort study. RESULTS Mothers with GDM displayed a significantly increased global placental DNA methylation (3.22 ± 0.63 vs. 3.00 ± 0.46 %; p = 0.013; ±SD). Bivariate logistic regression showed a highly significant positive correlation between global placental DNA methylation and the presence of GDM (p = 0.0009). Quintile stratification according to placental DNA 5mC levels revealed that the frequency of GDM was evenly distributed in quintiles 1-4 (2.9-5.3 %), whereas the frequency in the fifth quintile was significantly higher (10.7 %; p = 0.003). Bivariate logistic models adjusted for maternal age, BMI, ethnicity, recurrent miscarriages, and familiar diabetes predisposition clearly demonstrated an independent association between global placental DNA hypermethylation and GDM. Furthermore, an ANCOVA model considering known predictors of DNA methylation substantiated an independent association between GDM and placental DNA methylation. CONCLUSIONS This is the first study that employed a robust quantitative assessment of placental global DNA methylation in over a thousand placental samples. The study provides large scale evidence that placental global DNA hypermethylation is associated with GDM, independent of established risk factors.
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Affiliation(s)
- C. Reichetzeder
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
- Center for Cardiovascular Research (CCR), Campus Charité Mitte, University Hospital Charité, Berlin, Germany
| | - S. E. Dwi Putra
- Department of Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal, Potsdam 14558 Germany
- Faculty of Biotechnology, University of Surabaya, Surabaya, Indonesia
| | - T. Pfab
- Center for Cardiovascular Research (CCR), Campus Charité Mitte, University Hospital Charité, Berlin, Germany
- Diaverum Deutschland, Potsdam, Germany
| | - T. Slowinski
- Department of Nephrology, Campus Charité Mitte, University Hospital Charité, Berlin, Germany
| | - C. Neuber
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - B. Kleuser
- Department of Toxicology, Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany
| | - B. Hocher
- Department of Experimental Nutritional Medicine, Institute of Nutritional Science, University of Potsdam, Arthur-Scheunert-Allee 114-116, Nuthetal, Potsdam 14558 Germany
- Institut für Laboratoriumsmedizin, Berlin, Germany
- Department of Basic Medicine, Medical College of Hunan Normal University, Changsha, China
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24
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Joyce BT, Gao T, Zheng Y, Liu L, Zhang W, Dai Q, Shrubsole MJ, Hibler EA, Cristofanilli M, Zhang H, Yang H, Vokonas P, Cantone L, Schwartz J, Baccarelli A, Hou L. Prospective changes in global DNA methylation and cancer incidence and mortality. Br J Cancer 2016; 115:465-72. [PMID: 27351216 PMCID: PMC4985350 DOI: 10.1038/bjc.2016.205] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Revised: 05/31/2016] [Accepted: 06/07/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Methylation of repetitive elements Alu and LINE-1 in humans is considered a surrogate for global DNA methylation. Previous studies of blood-measured Alu/LINE-1 and cancer risk are inconsistent. METHODS We studied 1259 prospective methylation measurements from blood drawn 1-4 times from 583 participants from 1999 to 2012. We used Cox regression to evaluate time-dependent methylation as a biomarker for cancer risk and mortality, and linear regression to compare mean differences in methylation over time by cancer status and analyse associations between rate of methylation change and cancer. RESULTS Time-dependent LINE-1 methylation was associated with prostate cancer incidence (HR: 1.38, 95% CI: 1.01-1.88) and all-cancer mortality (HR: 1.41, 95% CI: 1.03-1.92). The first measurement of Alu methylation (HR: 1.39, 95% CI: 1.08-1.79) was associated with all-cancer mortality. Participants who ultimately developed cancer had lower mean LINE-1 methylation than cancer-free participants 10+ years pre-diagnosis (P<0.01). Rate of Alu methylation change was associated with all-cancer incidence (HR: 3.62, 95% CI: 1.09-12.10). CONCLUSIONS Our results add longitudinal data on blood Alu and LINE-1 methylation and cancer, and potentially contribute to their use as early-detection biomarkers. Future larger studies are needed and should account for the interval between blood sample collection and cancer diagnosis.
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Affiliation(s)
- Brian T Joyce
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA.,Division of Epidemiology/Biostatistics, School of Public Health, University of Illinois-Chicago, 1603 W. Taylor Street, Chicago, IL 60612, USA
| | - Tao Gao
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Yinan Zheng
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA.,Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Lei Liu
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Wei Zhang
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Qi Dai
- Vanderbilt University Medical Center, 2525 West End Avenue, Suite 319, Nashville, TN 37203, USA
| | - Martha J Shrubsole
- Vanderbilt University Medical Center, 2525 West End Avenue, Suite 319, Nashville, TN 37203, USA
| | - Elizabeth A Hibler
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Massimo Cristofanilli
- Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 676 N. St Clair Street, 8th Floor, Chicago, IL 60611, USA
| | - Hu Zhang
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
| | - Hushan Yang
- Department of Medical Oncology, Division of Population Science, Sidney Kimmel Cancer Center, Thomas Jefferson University, 834 Chestnut Street, Suite 314, Philadelphia, PA 19107, USA
| | - Pantel Vokonas
- VA Normative Aging Study, VA Boston Healthcare System, 150 South Huntington Avenue, Boston, MA 02130, USA.,Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA
| | - Laura Cantone
- Molecular Epidemiology and Environmental Epigenetics Laboratory, Department of Clinical Sciences and Community Health, Università degli Studi di Milano, San Barnaba 8, Milan 20122, Italy
| | - Joel Schwartz
- Department of Environmental Health, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
| | - Andrea Baccarelli
- Department of Environmental Health, Harvard School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA
| | - Lifang Hou
- Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA.,Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, 303 E. Chicago Avenue, Olson Pavilion 8350, Chicago, IL 60611, USA
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25
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Neven KY, Piola M, Angelici L, Cortini F, Fenoglio C, Galimberti D, Pesatori AC, Scarpini E, Bollati V. Repetitive element hypermethylation in multiple sclerosis patients. BMC Genet 2016; 17:84. [PMID: 27317098 PMCID: PMC4912727 DOI: 10.1186/s12863-016-0395-0] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 06/10/2016] [Indexed: 01/21/2023] Open
Abstract
Background Multiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-α, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-α methylation levels to evaluate their difference in a case–control setup and their role as a marker of disability. Results We obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for ‘EDSS = 1.0’ and ‘1.5 ≤ EDSS ≤ 2.5’ compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: ‘EDSS = 1.0’ and ‘1.5 ≤ EDSS ≤ 2.5’. Conclusions MS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further. Electronic supplementary material The online version of this article (doi:10.1186/s12863-016-0395-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- K Y Neven
- Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Lab, Università degli Studi di Milano, Milan, Italy.,Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium
| | - M Piola
- Neurology Unit, Saronno ASST Valle Olona Hospital, Saronno, Italy
| | - L Angelici
- Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Lab, Università degli Studi di Milano, Milan, Italy
| | - F Cortini
- Department of Preventive Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Epidemiology Unit, Milan, Italy
| | - C Fenoglio
- Department of Pathophysiology and Transplantation, Dino Ferrari Centre, Università degli Studi di Milano and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - D Galimberti
- Department of Pathophysiology and Transplantation, Dino Ferrari Centre, Università degli Studi di Milano and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - A C Pesatori
- Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Lab, Università degli Studi di Milano, Milan, Italy.,Department of Preventive Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Epidemiology Unit, Milan, Italy
| | - E Scarpini
- Department of Pathophysiology and Transplantation, Dino Ferrari Centre, Università degli Studi di Milano and Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - V Bollati
- Department of Clinical Sciences and Community Health, EPIGET - Epidemiology, Epigenetics and Toxicology Lab, Università degli Studi di Milano, Milan, Italy. .,Department of Preventive Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Epidemiology Unit, Milan, Italy. .,Department of Clinical Sciences and Community Health, Valentina Bollati, Università degli Studi di Milano, Via San Barnaba 8, 20122, Milan, Italy.
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Abstract
Aberrant DNA methylation pattern is a well-known epigenetic marker of cancer cells. Recently, aberrant methylation was also reported in the peripheral blood of cancer patients and it could potentially serve as a biomarker for cancer risk. We investigated the methylation pattern of LINE-1 and other repetitive DNA elements in peripheral blood of cutaneous melanoma patients in order to search for an association with clinical characteristics. The patient cohort was composed by 69 unrelated melanoma patients, 28 of whom were hereditary cases (with or without CDKN2A mutations) and 41 were isolated (sporadic) melanoma cases. Methylation of LINE-1 was evaluated by pyrosequencing, whereas additional repetitive DNA sequences were assessed using Illumina 450K methylation microarray. Melanoma patients exhibited a higher, albeit heterogeneous, LINE-1 methylation level compared with controls. Hereditary melanoma patients carrying CDKN2A mutations showed a hypermethylated pattern of both LINE-1 and repetitive DNA elements compared with other patients. In particular, the methylation level at one specific CpG of LINE-1 was found to be correlated with the occurrence of metastasis. Our data suggest that LINE-1 hypermethylation in peripheral blood of melanoma patients is a potential epigenetic biomarker for metastasis occurrence.
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Ghorbani M, Themis M, Payne A. Genome wide classification and characterisation of CpG sites in cancer and normal cells. Comput Biol Med 2015; 68:57-66. [PMID: 26615449 DOI: 10.1016/j.compbiomed.2015.09.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Revised: 09/16/2015] [Accepted: 09/29/2015] [Indexed: 11/30/2022]
Abstract
This study identifies common methylation patterns across different cancer types in an effort to identify common molecular events in diverse types of cancer cells and provides evidence for the sequence surrounding a CpG to influence its susceptibility to aberrant methylation. CpG sites throughout the genome were divided into four classes: sites that either become hypo or hyper-methylated in a variety cancers using all the freely available microarray data (HypoCancer and HyperCancer classes) and those found in a constant hypo (Never methylated class) or hyper-methylated (Always methylated class) state in both normal and cancer cells. Our data shows that most CpG sites included in the HumanMethylation450K microarray remain unmethylated in normal and cancerous cells; however, certain sites in all the cancers investigated become specifically modified. More detailed analysis of the sites revealed that majority of those in the never methylated class were in CpG islands whereas those in the HyperCancer class were mostly associated with miRNA coding regions. The sites in the Hypermethylated class are associated with genes involved in initiating or maintaining the cancerous state, being enriched for processes involved in apoptosis, and with transcription factors predicted to bind to these genes linked to apoptosis and tumourgenesis (notably including E2F). Further we show that more LINE elements are associated with the HypoCancer class and more Alu repeats are associated with the HyperCancer class. Motifs that classify the classes were identified to distinguish them based on the surrounding DNA sequence alone, and for the identification of DNA sequences that could render sites more prone to aberrant methylation in cancer cells. This provides evidence that the sequence surrounding a CpG site has an influence on whether a site is hypo or hyper methylated.
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Affiliation(s)
- Mohammadmersad Ghorbani
- Department of Computer Science, Brunel University, Uxbridge, Middlesex UB8 3PH, UK; Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute
| | - Michael Themis
- Department of Biosciences, Brunel University, Uxbridge, Middlesex UB8 3PH, UK
| | - Annette Payne
- Department of Computer Science, Brunel University, Uxbridge, Middlesex UB8 3PH, UK.
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LINE-1 in cancer: multifaceted functions and potential clinical implications. Genet Med 2015; 18:431-9. [DOI: 10.1038/gim.2015.119] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Accepted: 07/16/2015] [Indexed: 12/15/2022] Open
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Rerkasem K, Rattanatanyong P, Rerkasem A, Wongthanee A, Rungruengthanakit K, Mangklabruks A, Mutirangura A. Higher Alu methylation levels in catch-up growth in twenty-year-old offsprings. PLoS One 2015; 10:e0120032. [PMID: 25807557 PMCID: PMC4373937 DOI: 10.1371/journal.pone.0120032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 01/31/2015] [Indexed: 11/23/2022] Open
Abstract
Alu elements and long interspersed element-1 (LINE-1 or L1) are two major human intersperse repetitive sequences. Lower Alu methylation, but not LINE-1, has been observed in blood cells of people in old age, and in menopausal women having lower bone mass and osteoporosis. Nevertheless, Alu methylation levels also vary among young individuals. Here, we explored phenotypes at birth that are associated with Alu methylation levels in young people. In 2010, 249 twenty-years-old volunteers whose mothers had participated in a study association between birth weight (BW) and nutrition during pregnancy in 1990, were invited to take part in our present study. In this study, the LINE-1 and Alu methylation levels and patterns were measured in peripheral mononuclear cells and correlated with various nutritional parameters during intrauterine and postnatal period of offspring. This included the amount of maternal intake during pregnancy, the mother’s weight gain during pregnancy, birth weight, birth length, and the rate of weight gain in the first year of life. Catch-up growth (CUG) was defined when weight during the first year was >0.67 of the standard score, according to WHO data. No association with LINE-1 methylation was identified. The mean level of Alu methylation in the CUG group was significantly higher than those non-CUG (39.61% and 33.66 % respectively, P < 0.0001). The positive correlation between the history of CUG in the first year and higher Alu methylation indicates the role of Alu methylation, not only in aging cells, but also in the human growth process. Moreover, here is the first study that demonstrated the association between a phenotype during the newborn period and intersperse repetitive sequences methylation during young adulthood.
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Affiliation(s)
- Kittipan Rerkasem
- Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand; The Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
| | - Prakasit Rattanatanyong
- Center of Excellence of Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Amaraporn Rerkasem
- Department of Surgery, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Antika Wongthanee
- The Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand
| | | | - Ampica Mangklabruks
- The Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand; Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Apiwat Mutirangura
- Center of Excellence of Molecular Genetics of Cancer and Human Diseases, Department of Anatomy, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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King K, Murphy S, Hoyo C. Epigenetic regulation of Newborns' imprinted genes related to gestational growth: patterning by parental race/ethnicity and maternal socioeconomic status. J Epidemiol Community Health 2015; 69:639-47. [PMID: 25678712 DOI: 10.1136/jech-2014-204781] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 01/22/2015] [Indexed: 12/30/2022]
Abstract
BACKGROUND Children born to parents with lower income and education are at risk for obesity and later-life risk of common chronic diseases, and epigenetics has been hypothesised to link these associations. However, epigenetic targets are unknown. We focus on a cluster of well-characterised genomically imprinted genes because their monoallelic expression is regulated by DNA methylation at differentially methylated regions (DMRs), are critical in fetal growth, and DNA methylation patterns at birth have been associated with increased risk of birth weight extremes and overweight status or obesity in early childhood. METHODS We measured DNA methylation at DMRs regulating genomically imprinted domains (IGF2/H19, DLK1/MEG3, NNAT and PLAGL1) using umbilical cord blood leucocytes from 619 infants recruited in Durham, North Carolina in 2010-2011. We examined differences in DNA methylation levels by race/ethnicity of both parents, and the role that maternal socioeconomic status (SES) may play in the association between race/ethnic epigenetic differences. RESULTS Unadjusted race/ethnic differences only were evident for DMRs regulating MEG3 and IGF2; race/ethnic differences persisted in IGF2/H19 and NNAT after accounting for income and education. CONCLUSIONS Results suggest that parental factors may not only influence DNA methylation, but also do so in ways that vary by DMR. Findings support the hypothesis that epigenetics may link the observed lower SES during the prenatal period and poor outcomes such as low birth weight; lower birth weight has previously been associated with adult-onset chronic diseases and conditions that include cardiovascular diseases, diabetes, obesity and some cancers.
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Affiliation(s)
- Katherine King
- Environmental Public Health Division, U.S. Environmental Protection Agency, Chapel Hill, North Carolina, USA Department of Community and Family Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Susan Murphy
- Department of Obstetrics and Gynecology, Duke University, Durham, North Carolina, USA
| | - Cathrine Hoyo
- Department of Biological Sciences, North Carolina State University, Raleigh, North Carolina, USA
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Neale RE, Clark PJ, Fawcett J, Fritschi L, Nagler BN, Risch HA, Walters RJ, Crawford WJ, Webb PM, Whiteman DC, Buchanan DD. Association between hypermethylation of DNA repetitive elements in white blood cell DNA and pancreatic cancer. Cancer Epidemiol 2014; 38:576-82. [DOI: 10.1016/j.canep.2014.08.006] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Revised: 08/14/2014] [Accepted: 08/17/2014] [Indexed: 11/28/2022]
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Stigliano V, Sanchez-Mete L, Martayan A, Anti M. Early-onset colorectal cancer: A sporadic or inherited disease? World J Gastroenterol 2014; 20:12420-12430. [PMID: 25253942 PMCID: PMC4168075 DOI: 10.3748/wjg.v20.i35.12420] [Citation(s) in RCA: 95] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 03/18/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third most common cancer diagnosed worldwide. Although epidemiology data show a marked variability around the world, its overall incidence rate shows a slow but steady decrease, mainly in developed countries. Conversely, early-onset colorectal cancer appears to display an opposite trend with an overall prevalence in United States and European Union ranging from 3.0% and 8.6%. Colorectal cancer has a substantial proportion of familial cases. In particular, early age at onset is especially suggestive of hereditary predisposition. The clinicopathological and molecular features of colorectal cancer cases show a marked heterogeneity not only between early- and late-onset cases but also within the early-onset group. Two distinct subtypes of early-onset colorectal cancers can be identified: a “sporadic” subtype, usually without family history, and an inherited subtype arising in the context of well defined hereditary syndromes. The pathogenesis of the early-onset disease is substantially well characterized in the inherited subtype, which is mainly associated to the Lynch syndrome and occasionally to other rare mendelian diseases, whereas in the “sporadic” subtype the origin of the disease may be attributed to the presence of various common/rare genetic variants, so far largely unidentified, displaying variable penetrance. These variants are thought to act cumulatively to increase the risk of colorectal cancer, and presumably to also anticipate its onset. Efforts are ongoing in the attempt to unravel the intricate genetic basis of this “sporadic” early-onset disease. A better knowledge of molecular entities and pathways may impact on family-tailored prevention and clinical management strategies.
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Nzabarushimana E, Miousse IR, Shao L, Chang J, Allen AR, Turner J, Stewart B, Raber J, Koturbash I. Long-term epigenetic effects of exposure to low doses of 56Fe in the mouse lung. JOURNAL OF RADIATION RESEARCH 2014; 55:823-8. [PMID: 24585548 PMCID: PMC4100002 DOI: 10.1093/jrr/rru010] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/15/2023]
Abstract
Despite significant progress, the long-term health effects of exposure to high charge (Z) and energy (E) nuclei (HZEs) and the underlying mechanisms remain poorly understood. Mouse studies show that space missions can result in pulmonary pathological states. The goal of this study was to evaluate the pro-fibrotic and pro-carcinogenic effects of exposure to low doses of heavy iron ions ((56)Fe) in the mouse lung. Exposure to (56)Fe (600 MeV; 0.1, 0.2 and 0.4 Gy) resulted in minor pro-fibrotic changes, detected at the beginning of the fibrotic phase (22 weeks post exposure), which were exhibited as increased expression of chemokine Ccl3, and interleukin Il4. Epigenetic alterations were exhibited as global DNA hypermethylation, observed after exposure to 0.4 Gy. Cadm1, Cdh13, Cdkn1c, Mthfr and Sfrp1 were significantly hypermethylated after exposure to 0.1 Gy, while exposure to higher doses resulted in hypermethylation of Cdkn1c only. However, expression of these genes was not affected by any dose. Congruently with the observed patterns of global DNA methylation, DNA repetitive elements were hypermethylated after exposure to 0.4 Gy, with minor changes observed after exposure to lower doses. Importantly, hypermethylation of repetitive elements coincided with their transcriptional repression. The findings of this study will aid in understanding molecular determinants of pathological states associated with exposure to (56)Fe, as well as serve as robust biomarkers for the delayed effects of irradiation. Further studies are clearly needed to investigate the persistence and outcomes of molecular alterations long term after exposure.
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Affiliation(s)
- Etienne Nzabarushimana
- Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
| | - Isabelle R Miousse
- Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
| | - Lijian Shao
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
| | - Jianhui Chang
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
| | - Antiño R Allen
- Division of Radiation Health, Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
| | - Jennifer Turner
- Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA
| | - Blair Stewart
- Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA
| | - Jacob Raber
- Department of Behavioral Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA Department of Neurology, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA Division of Cancer Biology and Radiobiology, and Division of Neuroscience, ONPRC, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Rd, Portland, 97239-3098, OR, USA
| | - Igor Koturbash
- Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences, 4301 West Markham Street, #820-11, Little Rock, 72205-7199, AR, USA
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Sang Q, Li X, Wang H, Wang H, Zhang S, Feng R, Xu Y, Li Q, Zhao X, Xing Q, Jin L, He L, Wang L. Quantitative methylation level of the EPHX1 promoter in peripheral blood DNA is associated with polycystic ovary syndrome. PLoS One 2014; 9:e88013. [PMID: 24505354 PMCID: PMC3914883 DOI: 10.1371/journal.pone.0088013] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 01/03/2014] [Indexed: 11/18/2022] Open
Abstract
Steroid synthesis and metabolic pathways play important roles in the pathophysiology of PCOS, but until now there have been no studies on the methylation profiles of specific genes in steroid synthesis pathways that are known to be associated with PCOS. Here we used MassARRAY quantitative methylation analysis to determine the methylation levels of each CpG site or cluster in the promoters of EPHX1, SRD5A1, and CYP11A1 in 64 peripheral blood samples. We further examined the methylation level of EPHX1 in an independent cohort consisting of 116 people. Finally, we investigated the role of EPHX1 in steroidogenesis in the KGN cell line. For SRD5A1 and CYP11A1, there was no significant difference in methylation level between patients and controls. For EPHX1, however, the methylation levels of a few consecutive CpG sites and clusters were found to be significantly associated with PCOS. The methylation levels of a number of CpG clusters or sites were significantly lower in patients than in controls in the first cohort consisting of 64 people, such as clusters 13–14 (P<0.05), 15–16 (P<0.001), and 19–24 (P<0.001) and sites CpG_53 (P<0.01) and CpG_54 (P<0.05). Among differentiated methylation sites and clusters, the methylation levels of the CpG cluster 13–14 and CpG cluster 19–24 in PCOS patients were significantly lower than in controls in the second cohort of 116 people (P<0.05 for both). In addition, knockdown and overexpression experiments in KGN cells showed that EPHX1 can regulate estradiol concentrations, and this indicates a role for EPHX1 in steroidogenesis. Our study has demonstrated that methylation of the EPHX1 promoter might be associated with PCOS. This study provides direct evidence that methylation plays an important role in PCOS and demonstrates a novel role for EPHX1 in female reproduction.
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Affiliation(s)
- Qing Sang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Xin Li
- Department of Gynecology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China
| | - Haojue Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Huan Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | | | - Ruizhi Feng
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Yao Xu
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Qiaoli Li
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Xinzhi Zhao
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
| | - Qinghe Xing
- Institutes of Biomedical Science, Fudan University, Shanghai, China
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
| | - Lin He
- Institutes of Biomedical Science, Fudan University, Shanghai, China
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Lei Wang
- State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Institutes of Biomedical Science, Fudan University, Shanghai, China
- Bio-X Center, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
- * E-mail:
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Burdge GC, Calder PC. Does early n-3 fatty acid exposure alter DNA methylation in the developing human immune system? ACTA ACUST UNITED AC 2013. [DOI: 10.2217/clp.13.53] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Lind L, Penell J, Luttropp K, Nordfors L, Syvänen AC, Axelsson T, Salihovic S, van Bavel B, Fall T, Ingelsson E, Lind PM. Global DNA hypermethylation is associated with high serum levels of persistent organic pollutants in an elderly population. ENVIRONMENT INTERNATIONAL 2013; 59:456-61. [PMID: 23933504 DOI: 10.1016/j.envint.2013.07.008] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Revised: 07/05/2013] [Accepted: 07/10/2013] [Indexed: 05/20/2023]
Abstract
Dioxin exposure has experimentally been associated with changes in DNA methylation, an epigenetic change that is associated with disease. The present study aims to investigate if serum levels of dioxin and other persistent environmental pollutants are related to global DNA methylation in a human sample. In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (all aged 70), global DNA methylation was measured by the Luminometric Methylation Assay in 524 subjects. Twenty-three different POPs, including 16 PCBs, five pesticides, one dioxin (OCDD) and one brominated flame retardant (BDE47) were analysed by HRGC/HRMS. Ten single nucleotide polymorphisms (SNPs) in the Aryl hydrocarbon (Ah)-receptor were analysed by mini-sequencing. High levels of toxic equivalency (TEQ) for PCBs and dioxin were associated with DNA hypermethylation (p=0.030). This was mainly attributed to coplanar non-ortho PCBs. While no significant associations were found between DNA methylation and SNPs in the Ah-receptor, an interaction was found between the SNP rs2237297 and TEQ so that TEQ was associated with hypermethylation (p=0.009) only in subjects with one G-allele (n=103). Also high levels of the PCB126 congener, the OCDD, and the pesticide metabolite p,p'-DDE were related to DNA hypermethylation (p=0.01, 0.03 and 0.003, respectively). In conclusion, in a sample of elderly subjects, high TEQ including PCBs and the dioxin OCDD and high serum levels of PCB126, OCDD, and p,p'-DDE were related to global DNA hypermethylation in a cross-sectional analysis.
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Affiliation(s)
- Lars Lind
- Department of Medical Sciences, Cardiovascular Epidemiology, Uppsala University, Uppsala, Sweden
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