New DNA Methylation Markers and Global DNA Hypomethylation Are Associated with Oral Cancer Development

5524 Background: We have reported that DNA methyltransferase-3B (DNMT3B) gene expression is a strong predictor of OC dvlpt. Using high-throughput DNA methylation profiles of oral preneoplastic lesions (OPL), we identified 86 candidate genes that were hypermethylated in patients (pts) developing OC and suggested that a CpG island methylation phenotype may occur early during OC dvlpt. Our aim was to validate some of the candidate genes and to study the value of LINE1 repetitive element methylation, a surrogate of global DNA methylation, as biomarkers of risk to develop OC. Methods: Validation cohort included 40 pts with a median follow-up of 4.2 years, including 14 pts who developed OC. None of them were used in the discovery phase. Frozen OPL were collected prospectively and subject to DNA extraction. We performed a quantitative analysis of the degree of methylation of LINE1, and AGTR1, FOXI2, PENK, and HOXA9 promoters CpG sites using pyrosequencing. Results: The degree of methylation of AGTR1 (Mann-Whitney P<0.0001), FOXI2 (P=0.0002), PENK (P<0.0001), but not HOXA9 (P=0.0714) was significantly higher in pts who developed OC. On the contrary, LINE1 methylation was significantly lower in pts who developed OC (P<0.0001). The median percent of methylation was used to dichotomize the pts into high versus low methylation levels. Oral cancer-free survival (OCFS) was significantly worse in pts with high levels of AGTR1 (Log-rank P=0.0229), FOXI2 (P=0.0170), and PENK (P=0.0142) promoter methylation. No significant difference was found with HOXA9. A Methylation Index (MI) was developed by averaging the percent of methylation of AGTR1, FOXI2, and PENK promoters; pts with a high MI had a worse OCFS (P=0.0031). On the other hand, pts with low levels of LINE1 methylation had a significantly worse OCFS (P=0.0118). Finally, in 26 pts, a positive correlation was observed between DNMT3B gene expression levels and the MI (rho=0.65, P=0.0003); surprisingly, there was a negative correlation with LINE1 methylation (rho=-0.74, P<0.0001). Conclusions: AGTR1, FOXI2 and PENK promoter methylation may be associated with increased OC risk in pts with OPL and correlate with DNMT3B expression. Global DNA hypomethylation is an early event in OC dvlpt.

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Epigenetic Contribution and Genomic Imprinting Dlk1-Dio3 miRNAs in Systemic Lupus Erythematosus

Genes ◽

10.3390/genes12050680 ◽

2021 ◽

Vol 12 (5) ◽

pp. 680

Author(s):

Rujuan Dai ◽

Zhuang Wang ◽

S. Ansar Ahmed

Keyword(s):

Systemic Lupus Erythematosus ◽

Dna Methylation ◽

Lupus Erythematosus ◽

Critical Role ◽

Methylation Status ◽

Transcriptional Level ◽

Dna Hypomethylation ◽

Systemic Lupus ◽

Multiple Organs ◽

Genetic Imprinting

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease that afflicts multiple organs, especially kidneys and joints. In addition to genetic predisposition, it is now evident that DNA methylation and microRNAs (miRNAs), the two major epigenetic modifications, are critically involved in the pathogenesis of SLE. DNA methylation regulates promoter accessibility and gene expression at the transcriptional level by adding a methyl group to 5′ cytosine within a CpG dinucleotide. Extensive evidence now supports the importance of DNA hypomethylation in SLE etiology. miRNAs are small, non-protein coding RNAs that play a critical role in the regulation of genome expression. Various studies have identified the signature lupus-related miRNAs and their functional contribution to lupus incidence and progression. In this review, the mutual interaction between DNA methylation and miRNAs regulation in SLE is discussed. Some lupus-associated miRNAs regulate DNA methylation status by targeting the DNA methylation enzymes or methylation pathway-related proteins. On the other hand, DNA hyper- and hypo-methylation are linked with dysregulated miRNAs expression in lupus. Further, we specifically discuss the genetic imprinting Dlk1-Dio3 miRNAs that are subjected to DNA methylation regulation and are dysregulated in several autoimmune diseases, including SLE.

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PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

Diseases of the Esophagus ◽

10.1093/dote/doy089.ps02.176 ◽

2018 ◽

Vol 31 (Supplement_1) ◽

pp. 172-172

Author(s):

Yoshifumi Baba ◽

Taisuke Yagi ◽

Yuki Kiyozumi ◽

Yukiharu Hiyoshi ◽

Masaaki Iwatsuki ◽

...

Keyword(s):

Dna Methylation ◽

Immune Response ◽

Esophageal Cancer ◽

Methylation Level ◽

Cpg Island ◽

Surrogate Marker ◽

Esophageal Tumor ◽

Local Immune Response ◽

Dna Hypomethylation ◽

Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

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Artificial Light at Night of Different Spectral Compositions Differentially Affects Tumor Growth in Mice: Interaction With Melatonin and Epigenetic Pathways

Cancer Control ◽

10.1177/1073274818812908 ◽

2018 ◽

Vol 25 (1) ◽

pp. 107327481881290 ◽

Cited By ~ 12

Author(s):

A. E. Zubidat ◽

B. Fares ◽

F. Fares ◽

A. Haim

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Tumor Growth ◽

Short Wavelength ◽

Global Dna Methylation ◽

Artificial Light ◽

Dna Hypomethylation ◽

Light At Night ◽

Cancer Burden ◽

Melatonin Suppression

Lighting technology is rapidly advancing toward shorter wavelength illuminations that offer energy-efficient properties. Along with this advantage, the increased use of such illuminations also poses some health challenges, particularly breast cancer progression. Here, we evaluated the effects of artificial light at night (ALAN) of 4 different spectral compositions (500-595 nm) at 350 Lux on melatonin suppression by measuring its urine metabolite 6-sulfatoxymelatonin, global DNA methylation, tumor growth, metastases formation, and urinary corticosterone levels in 4T1 breast cancer cell-inoculated female BALB/c mice. The results revealed an inverse dose-dependent relationship between wavelength and melatonin suppression. Short wavelength increased tumor growth, promoted lung metastases formation, and advanced DNA hypomethylation, while long wavelength lessened these effects. Melatonin treatment counteracted these effects and resulted in reduced cancer burden. The wavelength suppression threshold for melatonin-induced tumor growth was 500 nm. These results suggest that short wavelength increases cancer burden by inducing aberrant DNA methylation mediated by the suppression of melatonin. Additionally, melatonin suppression and global DNA methylation are suggested as promising biomarkers for early diagnosis and therapy of breast cancer. Finally, ALAN may manifest other physiological responses such as stress responses that may challenge the survival fitness of the animal under natural environments.

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Genome-Wide Screening of Genes Regulated by DNA Methylation in Colon Cancer Development

PLoS ONE ◽

10.1371/journal.pone.0046215 ◽

2012 ◽

Vol 7 (10) ◽

pp. e46215 ◽

Cited By ~ 25

Author(s):

Sándor Spisák ◽

Alexandra Kalmár ◽

Orsolya Galamb ◽

Barna Wichmann ◽

Ferenc Sipos ◽

...

Keyword(s):

Dna Methylation ◽

Colon Cancer ◽

Cancer Development ◽

Genome Wide

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Early Pregnancy Exposure to Ambient Air Pollution among Late-Onset Preeclamptic Cases Is Associated with Placental DNA Hypomethylation of Specific Genes and Slower Placental Maturation

Toxics ◽

10.3390/toxics9120338 ◽

2021 ◽

Vol 9 (12) ◽

pp. 338

Author(s):

Karin Engström ◽

Yumjirmaa Mandakh ◽

Lana Garmire ◽

Zahra Masoumi ◽

Christina Isaxon ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Air Pollution ◽

Early Pregnancy ◽

Late Onset ◽

Dispersion Model ◽

Ambient Air ◽

Ambient Air Pollution ◽

Dna Hypomethylation ◽

Increased Risk

Exposure to ambient air pollution during pregnancy has been associated with an increased risk of preeclampsia (PE). Some suggested mechanisms behind this association are changes in placental DNA methylation and gene expression. The objective of this study was to identify how early pregnancy exposure to ambient nitrogen oxides (NOx) among PE cases and normotensive controls influence DNA methylation (EPIC array) and gene expression (RNA-seq). The study included placentas from 111 women (29 PE cases/82 controls) in Scania, Sweden. First-trimester NOx exposure was assessed at the participants’ residence using a dispersion model and categorized via median split into high or low NOx. Placental gestational epigenetic age was derived from the DNA methylation data. We identified six differentially methylated positions (DMPs, q < 0.05) comparing controls with low NOx vs. cases with high NOx and 14 DMPs comparing cases and controls with high NOx. Placentas with female fetuses showed more DMPs (N = 309) than male-derived placentas (N = 1). Placentas from PE cases with high NOx demonstrated gestational age deceleration compared to controls with low NOx (p = 0.034). No differentially expressed genes (DEGs, q < 0.05) were found. In conclusion, early pregnancy exposure to NOx affected placental DNA methylation in PE, resulting in placental immaturity and showing sexual dimorphism.

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The Arginine Methyltransferase PRMT6 Regulates DNA Methylation and Contributes to Global DNA Hypomethylation in Cancer

Cell Reports ◽

10.1016/j.celrep.2017.11.082 ◽

2017 ◽

Vol 21 (12) ◽

pp. 3390-3397 ◽

Cited By ~ 27

Author(s):

Nicolas Veland ◽

Swanand Hardikar ◽

Yi Zhong ◽

Sitaram Gayatri ◽

Jiameng Dan ◽

...

Keyword(s):

Dna Methylation ◽

Dna Hypomethylation ◽

Arginine Methyltransferase

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944 Systematic, Robust, Reversible DNA Methylation Precede Sporadic, Random Mutations in Colorectal Adenomadysplasia-Cancer Development

Gastroenterology ◽

10.1016/s0016-5085(15)30607-7 ◽

2015 ◽

Vol 148 (4) ◽

pp. S-182

Author(s):

Béla Molnár ◽

Bálint Péterfia ◽

Alexandra Kalmár ◽

Barnabás Wichmann ◽

Árpád V. Patai ◽

...

Keyword(s):

Dna Methylation ◽

Cancer Development

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Epigenetic modifications and human pathologies: cancer and CVD

Proceedings of The Nutrition Society ◽

10.1017/s0029665110003952 ◽

2010 ◽

Vol 70 (1) ◽

pp. 47-56 ◽

Cited By ~ 64

Author(s):

Susan J. Duthie

Keyword(s):

Dna Methylation ◽

Human Cancer ◽

Dna Methyltransferases ◽

Water Soluble ◽

Leafy Vegetables ◽

Dna Hypomethylation ◽

Human Diet ◽

Human Colon Cancer ◽

Increased Risk ◽

Risk Of Cancer

Epigenetic changes are inherited alterations in DNA that affect gene expression and function without altering the DNA sequence. DNA methylation is one epigenetic process implicated in human disease that is influenced by diet. DNA methylation involves addition of a 1-C moiety to cytosine groups in DNA. Methylated genes are not transcribed or are transcribed at a reduced rate. Global under-methylation (hypomethylation) and site-specific over-methylation (hypermethylation) are common features of human tumours. DNA hypomethylation, leading to increased expression of specific proto-oncogenes (e.g. genes involved in proliferation or metastasis) can increase the risk of cancer as can hypermethylation and reduced expression of tumour suppressor (TS) genes (e.g. DNA repair genes). DNA methyltransferases (DNMT), together with the methyl donor S-adenosylmethionine (SAM), facilitate DNA methylation. Abnormal DNA methylation is implicated not only in the development of human cancer but also in CVD. Polyphenols, a group of phytochemicals consumed in significant amounts in the human diet, effect risk of cancer. Flavonoids from tea, soft fruits and soya are potent inhibitors of DNMT in vitro, capable of reversing hypermethylation and reactivating TS genes. Folates, a group of water-soluble B vitamins found in high concentration in green leafy vegetables, regulate DNA methylation through their ability to generate SAM. People who habitually consume the lowest level of folate or with the lowest blood folate concentrations have a significantly increased risk of developing several cancers and CVD. This review describes how flavonoids and folates in the human diet alter DNA methylation and may modify the risk of human colon cancer and CVD.

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13-gene DNA Methylation Analysis from Oral Brushing: A Promising Non Invasive Tool in the Follow-up of Oral Cancer Patients

Journal of Clinical Medicine ◽

10.3390/jcm8122107 ◽

2019 ◽

Vol 8 (12) ◽

pp. 2107 ◽

Cited By ~ 4

Author(s):

Davide B. Gissi ◽

Achille Tarsitano ◽

Andrea Gabusi ◽

Roberto Rossi ◽

Giuseppe Attardo ◽

...

Keyword(s):

Dna Methylation ◽

Oral Cancer ◽

Cancer Treatment ◽

Sample Collection ◽

Methylation Analysis ◽

Non Invasive ◽

Locoregional Relapse ◽

Positive Score ◽

Dna Methylation Analysis

Background: This study aimed to evaluate the prognostic value of a non-invasive sampling procedure based on 13-gene DNA methylation analysis in the follow-up of patients previously treated for oral squamous cell carcinoma (OSCC). Methods: The study population included 49 consecutive patients treated for OSCC. Oral brushing sample collection was performed at two different times: before any cancer treatment in the tumor mass and during patient follow-up almost 6 months after OSCC treatment, within the regenerative area after OSCC resection. Each sample was considered positive or negative in relation to a predefined cut-off value. Results: Before any cancer treatment, 47/49 specimens exceeded the score and were considered as positive. Six months after OSCC resection, 16/49 specimens also had positive scores in the samples collected from the regenerative area. During the follow-up period, 7/49 patients developed locoregional relapse: 6/7 patients had a positive score in the regenerative area after OSCC resection. The presence of a positive score after oral cancer treatment was the most powerful variable related to the appearance of locoregional relapse. Conclusion: 13-gene DNA methylation analysis by oral brushing may have a clinical application as a prognostic non-invasive tool in the follow-up of patients surgically treated for OSCC.

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