Publications by authors named "Zdenko Herceg"

178 Publications

A concise review towards defining the exposome of oesophageal cancer in sub-Saharan Africa.

Environ Int 2021 12 17;157:106880. Epub 2021 Sep 17.

Department of Bioanalysis, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium; MYTOX-SOUTH, International Thematic Network, Ghent University, Ghent, Belgium; CRIG, Cancer Research Institute Ghent, Ghent, Belgium.

Context: Oesophageal cancer (EC) is among the common causes of illness and death among all cancers worldwide. Advanced EC has a poor prognosis, with worse outcomes observed in low-income settings. Oesophageal squamous cell carcinoma (ESCC) is the most common EC histology reported globally, with the highest ESCC incidence rates in the 'Asian Belt' and the African EC corridor. While the aetiology of ESCC is well-documented in the 'Asian belt', data for the African EC corridor and the entirety of sub-Saharan Africa (SSA) are fewer.

Objective: To help address gaps in ESCC aetiology in SSA, we critically evaluated evidence of lifestyle, environmental, and epigenetic factors associated with ESCC risk and discussed prospects of defining ESCC exposome.

Data Inclusion: Unlimited English and non-English articles search were made on PubMed Central and Web of Science databases from January 1970 to August 2021. In total, we retrieved 999 articles and considered meta-analyses, case-control, and cohort studies. The quality of individual studies was assessed using the Newcastle-Ottawa scale.

Data Extraction: Details extracted include the year of publication, country of origin, sample size, comparators, outcomes, study subjects, and designs.

Data Analysis: Together, we assessed 13 case-control studies and two meta-analyses for the effect of lifestyle or environmental exposures on ESCC risk. Again, we evaluated seven case-control studies and one meta-analysis regarding the role of epigenetics in ESCC tumorigenesis.

Results: In general, evidence of ESCC aetiology points to essential contributions of alcohol, tobacco, hot beverages, biomass fuel, and poor oral health/hygiene, although more precise risk characterisation remains necessary.

Conclusion: We conclude that ESCC in SSA is a multifactorial disease initiated by several external exposures that may induce aberrant epigenetic changes. The expanding aetiological research in this domain will be enhanced by evidence synthesis from classical and molecular epidemiological studies spanning the external and internal exposome.
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http://dx.doi.org/10.1016/j.envint.2021.106880DOI Listing
December 2021

Aflatoxin Exposure during Early Life Is Associated with Differential DNA Methylation in Two-Year-Old Gambian Children.

Int J Mol Sci 2021 Aug 20;22(16). Epub 2021 Aug 20.

School of Medicine, University of Leeds, Leeds LS2 9JT, UK.

: DNA methylation is an epigenetic control mechanism that may be altered by environmental exposures. We have previously reported that in utero exposure to the mycotoxin and liver carcinogen aflatoxin B1 from the maternal diet, as measured using biomarkers in the mothers' blood, was associated with differential DNA methylation in white blood cells of 6-month-old infants from The Gambia. : Here we examined aflatoxin B1-associated differential DNA methylation in white blood cells of 24-month-old children from the same population ( = 244), in relation to the child's dietary exposure assessed using aflatoxin albumin biomarkers in blood samples collected at 6, 12 and 18 months of age. HM450 BeadChip arrays were used to assess DNA methylation, with data compared to aflatoxin albumin adduct levels using two approaches; a continuous model comparing aflatoxin adducts measured in samples collected at 18 months to DNA methylation at 24 months, and a categorical time-dose model that took into account aflatoxin adduct levels at 6, 12 and 18 months, for comparison to DNA methylation at 24 months. : Geometric mean (95% confidence intervals) for aflatoxin albumin levels were 3.78 (3.29, 4.34) at 6 months, 25.1 (21.67, 29.13) at 12 months and 49.48 (43.34, 56.49) at 18 months of age. A number of differentially methylated CpG positions and regions were associated with aflatoxin exposure, some of which affected gene expression. Pathway analysis highlighted effects on genes involved with with inflammatory, signalling and growth pathways. : This study provides further evidence that exposure to aflatoxin in early childhood may impact on DNA methylation.
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http://dx.doi.org/10.3390/ijms22168967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8396526PMC
August 2021

IL6 and BCL3 Expression Are Potential Biomarkers in Esophageal Squamous Cell Carcinoma.

Front Oncol 2021 4;11:722417. Epub 2021 Aug 4.

Programa de Carcinogênese Molecular, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.

Esophageal squamous cell carcinoma (ESCC) ranks among the most lethal tumors worldwide, as a consequence of late detection and poor treatment response, evidencing the need for diagnosis anticipation and new therapeutic targets. First, we investigated the IL6 gene and protein expression in the esophagus of individuals without esophageal disorders (healthy), ESCC, and non-tumoral surrounding tissue (NTST). Our results showed that IL6 mRNA and protein expression is upregulated in tumor cells relative to NTST. In the TCGA dataset, we identified a set of genes whose expression was correlated with mRNA levels, including the antiapoptotic gene . By using an immortalized esophageal cell line, we confirmed that IL6 was capable of inducing expression in esophageal cells. BCL3 mRNA and protein are overexpressed in ESCC and NTST compared to healthy esophagus, and mRNA could distinguish the morphologically normal samples (healthy and NTST) with 100% sensitivity and 95.12% specificity. The spatial intratumoral heterogeneity of both and expression was evaluated, corroborating upregulation throughout the tumor, while tumor and NTST showed a consistent increase of expression relative to the healthy esophagus. Our study shows that IL6 overexpression seems to be a key event in ESCC carcinogenesis, contributing to ESCC through a homogeneous antiapoptotic signalling BCL3 overexpression, thus suggesting anti-IL6 therapies to be further considered for ESCC treatment. Finally, our data support the use of mRNA expression as a potential biomarker for ESCC detection.
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http://dx.doi.org/10.3389/fonc.2021.722417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371528PMC
August 2021

Epigenetic remodelling of enhancers in response to estrogen deprivation and re-stimulation.

Nucleic Acids Res 2021 Sep;49(17):9738-9754

Epigenetics Group, International Agency for Research on Cancer (IARC), 69372 Lyon Cedex 08, France.

Estrogen hormones are implicated in a majority of breast cancers and estrogen receptor alpha (ER), the main nuclear factor mediating estrogen signaling, orchestrates a complex molecular circuitry that is not yet fully elucidated. Here, we investigated genome-wide DNA methylation, histone acetylation and transcription after estradiol (E2) deprivation and re-stimulation to better characterize the ability of ER to coordinate gene regulation. We found that E2 deprivation mostly resulted in DNA hypermethylation and histone deacetylation in enhancers. Transcriptome analysis revealed that E2 deprivation leads to a global down-regulation in gene expression, and more specifically of TET2 demethylase that may be involved in the DNA hypermethylation following short-term E2 deprivation. Further enrichment analysis of transcription factor (TF) binding and motif occurrence highlights the importance of ER connection mainly with two partner TF families, AP-1 and FOX. These interactions take place in the proximity of E2 deprivation-mediated differentially methylated and histone acetylated enhancers. Finally, while most deprivation-dependent epigenetic changes were reversed following E2 re-stimulation, DNA hypermethylation and H3K27 deacetylation at certain enhancers were partially retained. Overall, these results show that inactivation of ER mediates rapid and mostly reversible epigenetic changes at enhancers, and bring new insight into early events, which may ultimately lead to endocrine resistance.
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http://dx.doi.org/10.1093/nar/gkab697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8464064PMC
September 2021

HPV Infection Leaves a DNA Methylation Signature in Oropharyngeal Cancer Affecting Both Coding Genes and Transposable Elements.

Cancers (Basel) 2021 Jul 20;13(14). Epub 2021 Jul 20.

Molecular Carcinogenesis Program, Brazilian National Cancer Institute, Rio de Janeiro CEP 20231-050, Brazil.

HPV oncoproteins can modulate DNMT1 expression and activity, and previous studies have reported both gene-specific and global DNA methylation alterations according to HPV status in head and neck cancer. However, validation of these findings and a more detailed analysis of the transposable elements (TEs) are still missing. Here we performed pyrosequencing to evaluate a 5-CpG methylation signature and Line1 methylation in an oropharyngeal squamous cell carcinoma (OPSCC) cohort. We further evaluated the methylation levels of the TEs, their correlation with gene expression and their impact on overall survival (OS) using the TCGA cohort. In our dataset, the 5-CpG signature distinguished HPV-positive and HPV-negative OPSCC with 66.67% sensitivity and 84.33% specificity. Line1 methylation levels were higher in HPV-positive cases. In the TCGA cohort, Line1, Alu and long terminal repeats (LTRs) showed hypermethylation in a frequency of 60.5%, 58.9% and 92.3%, respectively. and higher expression was observed in HPV-positive OPSCC, correlated with lower methylation levels of promoter-associated Alu and LTR, respectively, and independently associated with better OS. Based on our findings, we may conclude that a 5-CpG methylation signature can discriminate OPSCC according to HPV status with high accuracy and TEs are differentially methylated and may regulate gene expression in HPV-positive OPSCC.
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http://dx.doi.org/10.3390/cancers13143621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306428PMC
July 2021

Upper Aerodigestive Tract Squamous Cell Carcinomas Show Distinct Overall DNA Methylation Profiles and Different Molecular Mechanisms behind WNT Signaling Disruption.

Cancers (Basel) 2021 Jun 16;13(12). Epub 2021 Jun 16.

Molecular Carcinogenesis Program, Brazilian National Cancer Institute, Rua André Cavalcanti, 37-6° Andar, Bairro de Fátima, Rio de Janeiro 20231-050, Brazil.

Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected.
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http://dx.doi.org/10.3390/cancers13123014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234055PMC
June 2021

DNA Methylation Markers from Negative Surgical Margins Can Predict Recurrence of Oral Squamous Cell Carcinoma.

Cancers (Basel) 2021 Jun 11;13(12). Epub 2021 Jun 11.

Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil.

The identification of molecular markers in negative surgical margins of oral squamous cell carcinoma (OSCC) might help in identifying residual molecular aberrations, and potentially improve the prediction of prognosis. We performed an Infinium MethylationEPIC BeadChip array on 32 negative surgical margins stratified based on the status of tumor recurrence in order to identify recurrence-specific aberrant DNA methylation (DNAme) markers. We identified 2512 recurrence-associated Differentially Methylated Positions (DMPs) and 392 Differentially Methylated Regions (DMRs) which were enriched in cell signaling and cancer-related pathways. A set of 14-CpG markers was able to discriminate recurrent and non-recurrent cases with high specificity and sensitivity rates (AUC 0.98, = 3 × 10; CI: 0.95-1). A risk score based on the 14-CpG marker panel was applied, with cases classified within higher risk scores exhibiting poorer survival. The results were replicated using tumor-adjacent normal HNSCC samples from The Cancer Genome Atlas (TCGA). We identified residual DNAme aberrations in the negative surgical margins of OSCC patients, which could be informative for patient management by improving therapeutic intervention. This study proposes a novel DNAme-based 14-CpG marker panel as a promising predictor for tumor recurrence, which might contribute to improved decision-making for the personalized treatment of OSCC cases.
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http://dx.doi.org/10.3390/cancers13122915DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230600PMC
June 2021

Epigenome-wide association meta-analysis of DNA methylation with coffee and tea consumption.

Nat Commun 2021 05 14;12(1):2830. Epub 2021 May 14.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.

Coffee and tea are extensively consumed beverages worldwide which have received considerable attention regarding health. Intake of these beverages is consistently linked to, among others, reduced risk of diabetes and liver diseases; however, the mechanisms of action remain elusive. Epigenetics is suggested as a mechanism mediating the effects of dietary and lifestyle factors on disease onset. Here we report the results from epigenome-wide association studies (EWAS) on coffee and tea consumption in 15,789 participants of European and African-American ancestries from 15 cohorts. EWAS meta-analysis of coffee consumption reveals 11 CpGs surpassing the epigenome-wide significance threshold (P-value <1.1×10), which annotated to the AHRR, F2RL3, FLJ43663, HDAC4, GFI1 and PHGDH genes. Among them, cg14476101 is significantly associated with expression of the PHGDH and risk of fatty liver disease. Knockdown of PHGDH expression in liver cells shows a correlation with expression levels of genes associated with circulating lipids, suggesting a role of PHGDH in hepatic-lipid metabolism. EWAS meta-analysis on tea consumption reveals no significant association, only two CpGs annotated to CACNA1A and PRDM16 genes show suggestive association (P-value <5.0×10). These findings indicate that coffee-associated changes in DNA methylation levels may explain the mechanism of action of coffee consumption in conferring risk of diseases.
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http://dx.doi.org/10.1038/s41467-021-22752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121846PMC
May 2021

A Method to Investigate the Helicobacter pylori-Associated DNA Methylome.

Methods Mol Biol 2021 ;2283:75-81

Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France.

The protocol described here for methylome profiling consists of two parts. One is the experimental part for a genome-wide analysis of methylation level, and the other is the bioinformatics analysis of the methylome data. DNA methylation measurement is conducted using the commercially available array-based "Infinium Human Methylation 450K BeadChip" kit (or its updated version, Infinium MethylationEPICBeadChip). This BeadChip allows the high-throughput DNA methylation analysis suitable for genome-wide studies with large sample size. The results give intensities of the beads providing information on the unmethylated and methylated CpG sites. Bioinformatics data analysis involves reading the intensities as methylation values using R packages. Here, we provide a detailed analysis tool for each of the data analysis steps.
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http://dx.doi.org/10.1007/978-1-0716-1302-3_9DOI Listing
June 2021

Genome-Wide DNA Methylation Profiling of Esophageal Squamous Cell Carcinoma from Global High-Incidence Regions Identifies Crucial Genes and Potential Cancer Markers.

Cancer Res 2021 05 19;81(10):2612-2624. Epub 2021 Mar 19.

International Agency for Research on Cancer, Lyon, France.

Epigenetic mechanisms such as aberrant DNA methylation (DNAme) are known to drive esophageal squamous cell carcinoma (ESCC), yet they remain poorly understood. Here, we studied tumor-specific DNAme in ESCC cases from nine high-incidence countries of Africa, Asia, and South America. Infinium MethylationEPIC array was performed on 108 tumors and 51 normal tissues adjacent to the tumors (NAT) in the discovery phase, and targeted pyrosequencing was performed on 132 tumors and 36 NAT in the replication phase. Top genes for replication were prioritized by weighting methylation results using RNA-sequencing data from The Cancer Genome Atlas and GTEx and validated by qPCR. Methylome analysis comparing tumor and NAT identified 6,796 differentially methylated positions (DMP) and 866 differential methylated regions (DMR), with a 30% methylation (Δβ) difference. The majority of identified DMPs and DMRs were hypermethylated in tumors, particularly in promoters and gene-body regions of genes involved in transcription activation. The top three prioritized genes for replication, , and , had similar methylation differences in the discovery and replication sets. These genes were exclusively expressed in normal esophageal tissues in GTEx and downregulated in tumors. The specificity and sensitivity of these DNAme events in discriminating tumors from NAT were assessed. Our study identified novel, robust, and crucial tumor-specific DNAme events in ESCC tumors across several high-incidence populations of the world. Methylome changes identified in this study may serve as potential targets for biomarker discovery and warrant further functional characterization. SIGNIFICANCE: This largest genome-wide DNA methylation study on ESCC from high-incidence populations of the world identifies functionally relevant and robust DNAme events that could serve as potential tumor-specific markers. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/10/2612/F1.large.jpg.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-3445DOI Listing
May 2021

Identification of novel dysregulated circular RNAs in early-stage breast cancer.

J Cell Mol Med 2021 04 5;25(8):3912-3921. Epub 2021 Feb 5.

Department of Molecular Oncology, Cancer Institute (WIA), Chennai, India.

Breast cancer is a major cause of cancer-related death in women worldwide. Non-coding RNAs are a potential resource to be used as an early diagnostic biomarker for breast cancer. Circular RNAs are a recently identified group of non-coding RNA with a significant role in disease development with potential utility in diagnosis/prognosis in cancer. In this study, we identified 26 differentially expressed circular RNAs associated with early-stage breast cancer. RNA sequencing and two circRNA detection tools (find_circ and DCC) were used to understand the circRNA expression signature in breast cancer. We identified hsa_circ_0006743 (circJMJD1C) and hsa_circ_0002496 (circAPPBP1) to be significantly up-regulated in early-stage breast cancer tissues. Co-expression analysis identified four pairs of circRNA-miRNA (hsa_circ_0023990 : hsa-miR-548b-3p, hsa_circ_0016601 : hsa_miR-1246, hsa_circ_0001946 : hsa-miR-1299 and hsa_circ_0000117:hsa-miR-502-5p) having potential interaction. The miRNA target prediction and network analysis revealed mRNA possibly regulated by circRNAs. We have thus identified circRNAs of diagnostic implications in breast cancer and also observed circRNA-miRNA interaction which could be involved in breast cancer development.
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http://dx.doi.org/10.1111/jcmm.16324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051735PMC
April 2021

DNA methylation of insulin-like growth factor 2 and H19 cluster in cord blood and prenatal air pollution exposure to fine particulate matter.

Environ Health 2020 12 7;19(1):129. Epub 2020 Dec 7.

Centre for Environmental Sciences, Hasselt University, Agoralaan gebouw D, 3590 Diepenbeek, Hasselt, Belgium.

Background: The IGF2 (insulin-like growth factor 2) and H19 gene cluster plays an important role during pregnancy as it promotes both foetal and placental growth. We investigated the association between cord blood DNA methylation status of the IGF2/H19 gene cluster and maternal fine particulate matter exposure during fetal life. To the best of our knowledge, this is the first study investigating the association between prenatal PM exposure and newborn DNA methylation of the IGF2/H19.

Methods: Cord blood DNA methylation status of IGF2/H19 cluster was measured in 189 mother-newborn pairs from the ENVIRONAGE birth cohort (Flanders, Belgium). We assessed the sex-specific association between residential PM exposure during pregnancy and the methylation level of CpG loci mapping to the IGF2/H19 cluster, and identified prenatal vulnerability by investigating susceptible time windows of exposure. We also addressed the biological functionality of DNA methylation level in the gene cluster.

Results: Prenatal PM exposure was found to have genetic region-specific significant association with IGF2 and H19 during specific gestational weeks. The association was found to be sex-specific in both gene regions. Functionality of the DNA methylation was annotated by the association to fetal growth and cellular pathways.

Conclusions: The results of our study provided evidence that prenatal PM exposure is associated with DNA methylation in newborns' IGF2/H19. The consequences within the context of fetal development of future phenotyping should be addressed.
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http://dx.doi.org/10.1186/s12940-020-00677-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720562PMC
December 2020

Pan-cancer multi-omics analysis and orthogonal experimental assessment of epigenetic driver genes.

Genome Res 2020 10 22;30(10):1517-1532. Epub 2020 Sep 22.

Epigenetics Group, International Agency for Research on Cancer (IARC), 69008 Lyon, France.

The recent identification of recurrently mutated epigenetic regulator genes (ERGs) supports their critical role in tumorigenesis. We conducted a pan-cancer analysis integrating (epi)genome, transcriptome, and DNA methylome alterations in a curated list of 426 ERGs across 33 cancer types, comprising 10,845 tumor and 730 normal tissues. We found that, in addition to mutations, copy number alterations in ERGs were more frequent than previously anticipated and tightly linked to expression aberrations. Novel bioinformatics approaches, integrating the strengths of various driver prediction and multi-omics algorithms, and an orthogonal in vitro screen (CRISPR-Cas9) targeting all ERGs revealed genes with driver roles within and across malignancies and shared driver mechanisms operating across multiple cancer types and hallmarks. This is the largest and most comprehensive analysis thus far; it is also the first experimental effort to specifically identify ERG drivers (epidrivers) and characterize their deregulation and functional impact in oncogenic processes.
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http://dx.doi.org/10.1101/gr.268292.120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605261PMC
October 2020

Personalized early detection and prevention of breast cancer: ENVISION consensus statement.

Nat Rev Clin Oncol 2020 11 18;17(11):687-705. Epub 2020 Jun 18.

Department of Public Health, Erasmus MC, Rotterdam, Netherlands.

The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness-implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.
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http://dx.doi.org/10.1038/s41571-020-0388-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567644PMC
November 2020

A multi-omic analysis of birthweight in newborn cord blood reveals new underlying mechanisms related to cholesterol metabolism.

Metabolism 2020 09 15;110:154292. Epub 2020 Jun 15.

Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom; Medical Research Council-Health Protection Agency Centre for Environment and Health, Imperial College London, London, United Kingdom; Centre for Environmental Sciences, Hasselt University, Diepenbeek, Belgium. Electronic address:

Background: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited.

Methods: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations.

Results: This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns.

Conclusions: Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.
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http://dx.doi.org/10.1016/j.metabol.2020.154292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7450273PMC
September 2020

Arguments to Support a Viral Origin of Oral Squamous Cell Carcinoma in Non-Smoker and Non-Drinker Patients.

Front Oncol 2020 21;10:822. Epub 2020 May 21.

Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

In some western countries, an increasing incidence of oral squamous cell carcinoma (OSCC) has been observed in non-smoker non-drinker patients (NSND), mostly in women with HPV-negative OSCC. In the context of the unknown etiology and mechanisms of tumorigenesis of OSCC in NSND, we discuss data supporting the hypothesis of a viral origin not related to HPV. OSCC from NSND are characterized by an antiviral DNA methylation and gene expression signature. Based on the similar increasing incidence of oral tongue SCC (OTSCC) and oropharyngeal SCC (OPSCC) in young women and men respectively, we hypothesize that changes in sexual behaviors may lead to an increasing incidence of herpesvirus in the oral cavity, especially HSV-2, similarly to what has already been described in HPV-positive OPSCC. Because viral genome integration has not been detected in OSCC from NSND, a "hit and run" viral mechanism involving epigenome deregulation could therefore play a key role at early steps of oral carcinogenesis in this population of patients. In conclusion, epidemiological, clinical and molecular data supports a "hit and run" viral origin of OSCC from NSND.
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http://dx.doi.org/10.3389/fonc.2020.00822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253757PMC
May 2020

Genome-Wide DNA Methylation in Peripheral Blood and Long-Term Exposure to Source-Specific Transportation Noise and Air Pollution: The SAPALDIA Study.

Environ Health Perspect 2020 06 1;128(6):67003. Epub 2020 Jun 1.

Swiss Tropical and Public Health Institute, Basel, Switzerland.

Background: Few epigenome-wide association studies (EWAS) on air pollutants exist, and none have been done on transportation noise exposures, which also contribute to environmental burden of disease.

Objective: We performed mutually independent EWAS on transportation noise and air pollution exposures.

Methods: We used data from two time points of the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) from 1,389 participants contributing 2,542 observations. We applied multiexposure linear mixed-effects regressions with participant-level random intercept to identify significant Cytosine-phosphate-Guanine (CpG) sites and differentially methylated regions (DMRs) in relation to 1-y average aircraft, railway, and road traffic day-evening-night noise (Lden); nitrogen dioxide (); and particulate matter (PM) with aerodynamic diameter (). We performed candidate (CpG-based; cross-systemic phenotypes, combined into "allostatic load") and agnostic (DMR-based) pathway enrichment tests, and replicated previously reported air pollution EWAS signals.

Results: We found no statistically significant CpGs at false discovery rate . However, 14, 48, 183, 8, and 71 DMRs independently associated with aircraft, railway, and road traffic Lden; ; and , respectively, with minimally overlapping signals. Transportation Lden and air pollutants tendentially associated with decreased and increased methylation, respectively. We observed significant enrichment of candidate DNA methylation related to C-reactive protein and body mass index (aircraft, road traffic Lden, and ), renal function and "allostatic load" (all exposures). Agnostic functional networks related to cellular immunity, gene expression, cell growth/proliferation, cardiovascular, auditory, embryonic, and neurological systems development were enriched. We replicated increased methylation in cg08500171 () and decreased methylation in cg17629796 ().

Conclusions: Mutually independent DNA methylation was associated with source-specific transportation noise and air pollution exposures, with distinct and shared enrichments for pathways related to inflammation, cellular development, and immune responses. These findings contribute in clarifying the pathways linking these exposures and age-related diseases but need further confirmation in the context of mediation analyses. https://doi.org/10.1289/EHP6174.
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http://dx.doi.org/10.1289/EHP6174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263738PMC
June 2020

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.

Genome Med 2020 03 2;12(1):25. Epub 2020 Mar 2.

Centre de Recherche du Centre Hospitalier Universitaire de Sherbrooke (CHUS), Sherbrooke, QC, Canada.

Background: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children.

Methods: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung.

Results: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels.

Conclusions: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.
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http://dx.doi.org/10.1186/s13073-020-0716-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050134PMC
March 2020

The Promises and Challenges of Toxico-Epigenomics: Environmental Chemicals and Their Impacts on the Epigenome.

Environ Health Perspect 2020 01 17;128(1):15001. Epub 2020 Jan 17.

Epigenetics Group, International Agency for Research on Cancer (IARC), Lyon, France.

Background: It has been estimated that a substantial portion of chronic and noncommunicable diseases can be caused or exacerbated by exposure to environmental chemicals. Multiple lines of evidence indicate that early life exposure to environmental chemicals at relatively low concentrations could have lasting effects on individual and population health. Although the potential adverse effects of environmental chemicals are known to the scientific community, regulatory agencies, and the public, little is known about the mechanistic basis by which these chemicals can induce long-term or transgenerational effects. To address this question, epigenetic mechanisms have emerged as the potential link between genetic and environmental factors of health and disease.

Objectives: We present an overview of epigenetic regulation and a summary of reported evidence of environmental toxicants as epigenetic disruptors. We also discuss the advantages and challenges of using epigenetic biomarkers as an indicator of toxicant exposure, using measures that can be taken to improve risk assessment, and our perspectives on the future role of epigenetics in toxicology.

Discussion: Until recently, efforts to apply epigenomic data in toxicology and risk assessment were restricted by an incomplete understanding of epigenomic variability across tissue types and populations. This is poised to change with the development of new tools and concerted efforts by researchers across disciplines that have led to a better understanding of epigenetic mechanisms and comprehensive maps of epigenomic variation. With the foundations now in place, we foresee that unprecedented advancements will take place in the field in the coming years. https://doi.org/10.1289/EHP6104.
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http://dx.doi.org/10.1289/EHP6104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015548PMC
January 2020

Human mitochondrial DNA is extensively methylated in a non-CpG context.

Nucleic Acids Res 2019 11;47(19):10072-10085

Epigenetics Group, International Agency for Research on Cancer (IARC), 69372 Lyon Cedex 08, France.

Mitochondrial dysfunction plays critical roles in cancer development and related therapeutic response; however, exact molecular mechanisms remain unclear. Recently, alongside the discovery of mitochondrial-specific DNA methyltransferases, global and site-specific methylation of the mitochondrial genome has been described. Investigation of any functional consequences however remains unclear and debated due to insufficient evidence of the quantitative degree and frequency of mitochondrial DNA (mtDNA) methylation. This study uses WGBS to provide the first quantitative report of mtDNA methylation at single base pair resolution. The data show that mitochondrial genomes are extensively methylated predominantly at non-CpG sites. Importantly, these methylation patterns display notable differences between normal and cancer cells. Furthermore, knockdown of DNA methyltransferase enzymes resulted in a marked global reduction of mtDNA methylation levels, indicating these enzymes may be associated with the establishment and/or maintenance of mtDNA methylation. DNMT3B knockdown cells displayed a comparatively pronounced global reduction in mtDNA methylation with concomitant increases in gene expression, suggesting a potential functional link between methylation and gene expression. Together these results demonstrate reproducible, non-random methylation patterns of mtDNA and challenge the notion that mtDNA is lowly methylated. This study discusses key differences in methodology that suggest future investigations must allow for techniques that assess both CpG and non-CpG methylation.
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http://dx.doi.org/10.1093/nar/gkz762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821263PMC
November 2019

DNA hypermethylation is associated with invasive phenotype of malignant melanoma.

Exp Dermatol 2020 01 14;29(1):39-50. Epub 2019 Nov 14.

Public Health Research Institute, University of Debrecen, Debrecen, Hungary.

Tumor cell invasion is one of the key processes during cancer progression, leading to life-threatening metastatic lesions in melanoma. As methylation of cancer-related genes plays a fundamental role during tumorigenesis and may lead to cellular plasticity which promotes invasion, our aim was to identify novel epigenetic markers on selected invasive melanoma cells. Using Illumina BeadChip assays and Affymetrix Human Gene 1.0 microarrays, we explored the DNA methylation landscape of selected invasive melanoma cells and examined the impact of DNA methylation on gene expression patterns. Our data revealed predominantly hypermethylated genes in the invasive cells affecting the neural crest differentiation pathway and regulation of the actin cytoskeleton. Integrative analysis of the methylation and gene expression profiles resulted in a cohort of hypermethylated genes (IL12RB2, LYPD6B, CHL1, SLC9A3, BAALC, FAM213A, SORCS1, GPR158, FBN1 and ADORA2B) with decreased expression. On the other hand, hypermethylation in the gene body of the EGFR and RBP4 genes was positively correlated with overexpression of the genes. We identified several methylation changes that can have role during melanoma progression, including hypermethylation of the promoter regions of the ARHGAP22 and NAV2 genes that are commonly altered in locally invasive primary melanomas as well as during metastasis. Interestingly, the down-regulation of the methylcytosine dioxygenase TET2 gene, which regulates DNA methylation, was associated with hypermethylated promoter region of the gene. This can probably lead to the observed global hypermethylation pattern of invasive cells and might be one of the key changes during the development of malignant melanoma cells.
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http://dx.doi.org/10.1111/exd.14047DOI Listing
January 2020

Maternal Gestational Diabetes Mellitus and Newborn DNA Methylation: Findings From the Pregnancy and Childhood Epigenetics Consortium.

Diabetes Care 2020 01 10;43(1):98-105. Epub 2019 Oct 10.

Population Health Science, Bristol Medical School, University of Bristol, Bristol, U.K.

Objective: Maternal gestational diabetes mellitus (GDM) has been associated with adverse outcomes in the offspring. Growing evidence suggests that the epigenome may play a role, but most previous studies have been small and adjusted for few covariates. The current study meta-analyzed the association between maternal GDM and cord blood DNA methylation in the Pregnancy and Childhood Epigenetics (PACE) consortium.

Research Design And Methods: Seven pregnancy cohorts (3,677 mother-newborn pairs [317 with GDM]) contributed results from epigenome-wide association studies, using DNA methylation data acquired by the Infinium HumanMethylation450 BeadChip array. Associations between GDM and DNA methylation were examined using robust linear regression, with adjustment for potential confounders. Fixed-effects meta-analyses were performed using METAL. Differentially methylated regions (DMRs) were identified by taking the intersection of results obtained using two regional approaches: comb-p and DMRcate.

Results: Two DMRs were identified by both comb-p and DMRcate. Both regions were hypomethylated in newborns exposed to GDM in utero compared with control subjects. One DMR (chr 1: 248100345-248100614) was located in the promoter, and the other (chr 10: 135341870-135342620) was located in the gene body of . Individual CpG analyses did not reveal any differentially methylated loci based on a false discovery rate-adjusted value threshold of 0.05.

Conclusions: Maternal GDM was associated with lower cord blood methylation levels within two regions, including the promoter of , a gene associated with autism spectrum disorder, and the gene body of , which is upregulated in type 1 and type 2 diabetes. Future studies are needed to understand whether these associations are causal and possible health consequences.
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http://dx.doi.org/10.2337/dc19-0524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925578PMC
January 2020

In vitro transformation of primary human hepatocytes: Epigenetic changes and stemness properties.

Exp Cell Res 2019 11 23;384(2):111643. Epub 2019 Sep 23.

INSERM U1052, CNRS 5286, Univ Lyon, Université Claude Bernard Lyon 1, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, F-69000, Lyon, France. Electronic address:

Human hepatocarcinogenesis is a complex process with many unresolved issues, including the cell of origin (differentiated and/or progenitor/stem cells) and the initial steps leading to tumor development. With the aim of providing new tools for studying hepatocellular carcinoma initiation and progression, we developed an innovative model based on primary human hepatocytes (PHHs) lentivirus-transduced with SV40, HRAS with or without hTERT. The differentiation status of these transduced-PHHs was characterized by RNA sequencing (including lncRNAs), and the expression of some differentiation markers confirmed by RT-qPCR and immunofluorescence. In addition, their transformation capacity was assessed by colony formation in soft agar and tumorigenicity evaluated in immune-deficient mice. The co-expression of SV40 and HRAS in PHHs, in association or not with hTERT, led to the emergence of transformed clones. These clones exhibited a poorly differentiated cell phenotype with expression of stemness and mesenchymal-epithelial transition markers and gave rise to cancer stem cell subpopulations. In vivo, they resulted in poorly differentiated hepatocellular carcinomas with a reactivation of endogenous hTERT. These experiments demonstrate for the first time that non-cycling human mature hepatocytes can be permissive to in vitro transformation. This cellular tool provides the first comprehensive in vitro model for identifying genetic/epigenetic changes driving human hepatocarcinogenesis.
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http://dx.doi.org/10.1016/j.yexcr.2019.111643DOI Listing
November 2019

Comparison of smoking-related DNA methylation between newborns from prenatal exposure and adults from personal smoking.

Epigenomics 2019 10 19;11(13):1487-1500. Epub 2019 Sep 19.

Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for exposure in newborns is unknown. We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.
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http://dx.doi.org/10.2217/epi-2019-0066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836223PMC
October 2019

Antagonistic and synergistic epigenetic modulation using orthologous CRISPR/dCas9-based modular system.

Nucleic Acids Res 2019 10;47(18):9637-9657

Department of Biology, Division of Molecular Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, 10000 Zagreb, Croatia.

Establishing causal relationship between epigenetic marks and gene transcription requires molecular tools, which can precisely modify specific genomic regions. Here, we present a modular and extensible CRISPR/dCas9-based toolbox for epigenetic editing and direct gene regulation. It features a system for expression of orthogonal dCas9 proteins fused to various effector domains and includes a multi-gRNA system for simultaneous targeting dCas9 orthologs to up to six loci. The C- and N-terminal dCas9 fusions with DNMT3A and TET1 catalytic domains were thoroughly characterized. We demonstrated simultaneous use of the DNMT3A-dSpCas9 and TET1-dSaCas9 fusions within the same cells and showed that imposed cytosine hyper- and hypo-methylation altered level of gene transcription if targeted CpG sites were functionally relevant. Dual epigenetic manipulation of the HNF1A and MGAT3 genes, involved in protein N-glycosylation, resulted in change of the glycan phenotype in BG1 cells. Furthermore, simultaneous targeting of the TET1-dSaCas9 and VPR-dSpCas9 fusions to the HNF1A regulatory region revealed strong and persistent synergistic effect on gene transcription, up to 30 days following cell transfection, suggesting involvement of epigenetic mechanisms in maintenance of the reactivated state. Also, modulation of dCas9 expression effectively reduced off-target effects while maintaining the desired effects on target regions.
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http://dx.doi.org/10.1093/nar/gkz709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6765142PMC
October 2019

Smoking-associated DNA methylation changes: no smoke without fire.

Epigenomics 2019 08 24;11(10):1117-1119. Epub 2019 Jul 24.

Achutha Menon Centre for Health Science Studies, Sree Chitra Tirunal Institute for Medical Sciences & Technology, Thiruvananthapuram, Kerala, India.

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http://dx.doi.org/10.2217/epi-2019-0136DOI Listing
August 2019

Prenatal Particulate Air Pollution and DNA Methylation in Newborns: An Epigenome-Wide Meta-Analysis.

Environ Health Perspect 2019 05 31;127(5):57012. Epub 2019 May 31.

20 Barcelona Institute for Global Health (ISGlobal) , Barcelona, Spain.

Background: Prenatal exposure to air pollution has been associated with childhood respiratory disease and other adverse outcomes. Epigenetics is a suggested link between exposures and health outcomes.

Objectives: We aimed to investigate associations between prenatal exposure to particulate matter (PM) with diameter [Formula: see text] ([Formula: see text]) or [Formula: see text] ([Formula: see text]) and DNA methylation in newborns and children.

Methods: We meta-analyzed associations between exposure to [Formula: see text] ([Formula: see text]) and [Formula: see text] ([Formula: see text]) at maternal home addresses during pregnancy and newborn DNA methylation assessed by Illumina Infinium HumanMethylation450K BeadChip in nine European and American studies, with replication in 688 independent newborns and look-up analyses in 2,118 older children. We used two approaches, one focusing on single cytosine-phosphate-guanine (CpG) sites and another on differentially methylated regions (DMRs). We also related PM exposures to blood mRNA expression.

Results: Six CpGs were significantly associated [false discovery rate (FDR) [Formula: see text]] with prenatal [Formula: see text] and 14 with [Formula: see text] exposure. Two of the [Formula: see text] CpGs mapped to FAM13A (cg00905156) and NOTCH4 (cg06849931) previously associated with lung function and asthma. Although these associations did not replicate in the smaller newborn sample, both CpGs were significant ([Formula: see text]) in 7- to 9-y-olds. For cg06849931, however, the direction of the association was inconsistent. Concurrent [Formula: see text] exposure was associated with a significantly higher NOTCH4 expression at age 16 y. We also identified several DMRs associated with either prenatal [Formula: see text] and or [Formula: see text] exposure, of which two [Formula: see text] DMRs, including H19 and MARCH11, replicated in newborns.

Conclusions: Several differentially methylated CpGs and DMRs associated with prenatal PM exposure were identified in newborns, with annotation to genes previously implicated in lung-related outcomes. https://doi.org/10.1289/EHP4522.
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http://dx.doi.org/10.1289/EHP4522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792178PMC
May 2019

Blood DNA methylation and breast cancer risk: a meta-analysis of four prospective cohort studies.

Breast Cancer Res 2019 05 17;21(1):62. Epub 2019 May 17.

Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, USA.

Background: Environmental and genetic factors play an important role in the etiology of breast cancer. Several small blood-based DNA methylation studies have reported risk associations with methylation at individual CpGs and average methylation levels; however, these findings require validation in larger prospective cohort studies. To investigate the role of blood DNA methylation on breast cancer risk, we conducted a meta-analysis of four prospective cohort studies, including a total of 1663 incident cases and 1885 controls, the largest study of blood DNA methylation and breast cancer risk to date.

Methods: We assessed associations with methylation at 365,145 CpGs present in the HumanMethylation450 (HM450K) Beadchip, after excluding CpGs that did not pass quality controls in all studies. Each of the four cohorts estimated odds ratios (ORs) and 95% confidence intervals (CI) for the association between each individual CpG and breast cancer risk. In addition, each study assessed the association between average methylation measures and breast cancer risk, adjusted and unadjusted for cell-type composition. Study-specific ORs were combined using fixed-effect meta-analysis with inverse variance weights. Stratified analyses were conducted by age at diagnosis (< 50, ≥ 50), estrogen receptor (ER) status (+/-), and time since blood collection (< 5, 5-10, > 10 years). The false discovery rate (q value) was used to account for multiple testing.

Results: The average age at blood draw ranged from 52.2 to 62.2 years across the four cohorts. Median follow-up time ranged from 6.6 to 8.4 years. The methylation measured at individual CpGs was not associated with breast cancer risk (q value > 0.59). In addition, higher average methylation level was not associated with risk of breast cancer (OR = 0.94, 95% CI = 0.85, 1.05; P = 0.26; P for study heterogeneity = 0.86). We found no evidence of modification of this association by age at diagnosis (P = 0.17), ER status (P = 0.88), time since blood collection (P = 0.98), or CpG location (P = 0.98).

Conclusions: Our data indicate that DNA methylation measured in the blood prior to breast cancer diagnosis in predominantly postmenopausal women is unlikely to be associated with substantial breast cancer risk on the HM450K array. Larger studies or with greater methylation coverage are needed to determine if associations exist between blood DNA methylation and breast cancer risk.
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http://dx.doi.org/10.1186/s13058-019-1145-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525390PMC
May 2019
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