scholarly journals Investigating DNA methylation as a potential mediator between pigmentation genes, pigmentary traits and skin cancer

2020 ◽  
Author(s):  
Carolina Bonilla ◽  
Bernardo Bertoni ◽  
Josine L Min ◽  
Gibran Hemani ◽  
Hannah R Elliott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Skin Cancer ◽  
Cell Carcinoma ◽  
Whole Blood ◽  
Sun Exposure ◽  
European Ancestry ◽  
Hair Colour ◽  
Red Hair ◽  
Increased Risk

AbstractBackgroundIncidence rates for melanoma and non-melanoma skin cancer (NMSC), which includes basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), have been steadily increasing in all populations. Populations of European ancestry exhibit the highest rates and therefore, have been widely studied. Pigmentation characteristics are well-known risk factors for skin cancer, particularly fair skin, red hair, blue eyes and the inability to tan. Polymorphisms in established pigmentation-related genes have been associated with these traits and with an increased risk of malignancy. However, the functional relationship between genetic variation and disease is still unclear, with the exception of red hair colour variants in the melanocortin 1 receptor (MC1R) gene.ObjectivesThe aim of this study was to explore the possibility that non-coding pigmentation SNPs are associated with pigmentary traits and skin cancer via DNA methylation (DNAm).Methods and ResultsUsing a meta-GWAS of whole blood DNAm from 36 European cohorts (N=27,750; the Genetics of DNA Methylation Consortium, GoDMC), we found that 19 out of 27 pigmentation-associated SNPs distributed within 10 genes (ASIP, BNC2, IRF4, HERC2, MC1R, OCA2, SLC24A4, SLC24A5, SLC45A2, TYR) were associated with 391 DNAm sites across 30 genomic regions. We selected 25 DNAm sites for further analysis.We examined the effect of the chosen DNAm sites on pigmentation traits, sun exposure phenotypes, and skin cancer, and on gene expression in whole blood. We found an association of decreased DNAm at cg07402062 with red hair in the Avon Longitudinal Study of Parents and Children (ALSPAC), and a strong positive association of DNAm at this and correlated sites with higher expression of SPIRE2. Additionally, we investigated the association of gene expression in skin with pigmentation traits and skin cancer. The expression of ASIP, FAM83C, NCOA6, CDK10, and EXOC2 was associated with hair colour, whilst that of ASIP and CDK10 also had an effect on melanoma and BCC.ConclusionsOur results indicate that DNAm and expression of genes in the 16q24.3 and 20q11.22 regions, deserve to be further investigated as potential mediators of the relationship between genetic variants, pigmentation/sun exposure phenotypes, and some types of skin cancer.

scholarly journals Epigenome-wide association study of whole blood gene expression in Framingham Heart Study participants provides molecular insight into the potential role of CHRNA5 in cigarette smoking-related lung diseases

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chen Yao ◽  
Roby Joehanes ◽  
Rory Wilson ◽  
Toshiko Tanaka ◽  
Luigi Ferrucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Dna Methylation ◽  
Cigarette Smoking ◽  
Association Study ◽  
Whole Blood ◽  
Lung Diseases ◽  
Epigenetic Modification ◽  
Blood Gene Expression ◽  
Increased Risk

Abstract Background DNA methylation is a key epigenetic modification that can directly affect gene regulation. DNA methylation is highly influenced by environmental factors such as cigarette smoking, which is causally related to chronic obstructive pulmonary disease (COPD) and lung cancer. To date, there have been few large-scale, combined analyses of DNA methylation and gene expression and their interrelations with lung diseases. Results We performed an epigenome-wide association study of whole blood gene expression in ~ 6000 individuals from four cohorts. We discovered and replicated numerous CpGs associated with the expression of cis genes within 500 kb of each CpG, with 148 to 1,741 cis CpG-transcript pairs identified across cohorts. We found that the closer a CpG resided to a transcription start site, the larger its effect size, and that 36% of cis CpG-transcript pairs share the same causal genetic variant. Mendelian randomization analyses revealed that hypomethylation and lower expression of CHRNA5, which encodes a smoking-related nicotinic receptor, are causally linked to increased risk of COPD and lung cancer. This putatively causal relationship was further validated in lung tissue data. Conclusions Our results provide a large and comprehensive association study of whole blood DNA methylation with gene expression. Expression platform differences rather than population differences are critical to the replication of cis CpG-transcript pairs. The low reproducibility of trans CpG-transcript pairs suggests that DNA methylation regulates nearby rather than remote gene expression. The putatively causal roles of methylation and expression of CHRNA5 in relation to COPD and lung cancer provide evidence for a mechanistic link between patterns of smoking-related epigenetic variation and lung diseases, and highlight potential therapeutic targets for lung diseases and smoking cessation.

Hugh Jackman vs. Skin Cancer Awareness Month: Promoting Public Interest in Basal Cell Carcinoma (Preprint)

2020 ◽  
Author(s):  
Trevor Torgerson ◽  
Jennifer Austin ◽  
Jam Khojasteh ◽  
Matt Vassar
Keyword(s):  
Social Media ◽  
Skin Cancer ◽  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Basal Cell ◽  
Moving Average ◽  
Public Awareness ◽  
Sun Exposure ◽  
Cancer Awareness ◽  
Autoregressive Integrated Moving Average

BACKGROUND Public awareness for BCC is particularly important, as its major risk factors — increased sun exposure and number of sunburns — are largely preventable. OBJECTIVE Determine whether social media posts from celebrities has an affect on public awareness of basal cell carcinoma. METHODS We used Google Trends to investigate whether public awareness for basal cell carcinoma (BCC) increased following social media posts from Hugh Jackman. To forecast the expected search interest for BCC, melanoma and sunscreen in the event that each celebrity had not posted on social media, we used the autoregressive integrated moving average (ARIMA) algorithm. RESULTS We found that social media posts from Hugh Jackman, a well-known actor, increased relative search interest above the expected search interest calculated using an ARIMA forecasting model. CONCLUSIONS Our results also suggest that increasing awareness by Skin Cancer Awareness Month may be less effective for BCC, but a celebrity spokesperson has the potential to increase awareness. BCC is largely preventable, so increasing awareness could lead to a decrease in incidence.

scholarly journals DNA methylome signatures of prenatal exposure to synthetic glucocorticoids in hippocampus and peripheral whole blood of female guinea pigs in early life

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Aya Sasaki ◽  
Margaret E. Eng ◽  
Abigail H. Lee ◽  
Alisa Kostaki ◽  
Stephen G. Matthews
Keyword(s):  
Dna Methylation ◽  
Whole Blood ◽  
Guinea Pigs ◽  
Critical Role ◽  
Methylation Status ◽  
Peripheral Tissues ◽  
Epigenetic Biomarkers ◽  
Differentially Methylated Genes ◽  
Increased Risk ◽  
Synthetic Glucocorticoids

AbstractSynthetic glucocorticoids (sGC) are administered to women at risk of preterm delivery, approximately 10% of all pregnancies. In animal models, offspring exposed to elevated glucocorticoids, either by administration of sGC or endogenous glucocorticoids as a result of maternal stress, show increased risk of developing behavioral, endocrine, and metabolic dysregulation. DNA methylation may play a critical role in long-lasting programming of gene regulation underlying these phenotypes. However, peripheral tissues such as blood are often the only accessible source of DNA for epigenetic analyses in humans. Here, we examined the hypothesis that prenatal sGC administration alters DNA methylation signatures in guinea pig offspring hippocampus and whole blood. We compared these signatures across the two tissue types to assess epigenetic biomarkers of common molecular pathways affected by sGC exposure. Guinea pigs were treated with sGC or saline in late gestation. Genome-wide modifications of DNA methylation were analyzed at single nucleotide resolution using reduced representation bisulfite sequencing in juvenile female offspring. Results indicate that there are tissue-specific as well as common methylation signatures of prenatal sGC exposure. Over 90% of the common methylation signatures associated with sGC exposure showed the same directionality of change in methylation. Among differentially methylated genes, 134 were modified in both hippocampus and blood, of which 61 showed methylation changes at identical CpG sites. Gene pathway analyses indicated that prenatal sGC exposure alters the methylation status of gene clusters involved in brain development. These data indicate concordance across tissues of epigenetic programming in response to alterations in glucocorticoid signaling.

scholarly journals Oxidative stress underlies heritable impacts of paternal cigarette smoke exposure

2019 ◽  
Author(s):  
Patrick J Murphy ◽  
Jingtao Guo ◽  
Timothy G Jenkins ◽  
Emma R James ◽  
John R Hoidal ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Dna Methylation ◽  
Cigarette Smoke ◽  
Cigarette Smoke Exposure ◽  
Epigenetic Changes ◽  
Sperm Dna ◽  
Increased Risk ◽  
Paternal Smoking ◽  
Sperm Dna Methylation

SUMMARYPaternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. This study used mouse models to evaluate: 1) what impact paternal CS exposure has on sperm DNA methylation (DNAme), 2) whether sperm DNAme changes persist after CS exposure ends, 3) the degree to which DNAme and gene expression changes occur in offspring and 4) the mechanism underlying impacts of CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking causes changes in neural DNAme and gene expression in offspring. Remarkably, the effects of CS exposure are largely recapitulated in oxidative stress-compromised Nrf2-/- mice and their offspring, independent of paternal smoking. These results demonstrate that paternal CS exposure impacts offspring phenotype and that oxidative stress underlies CS induced heritable epigenetic changes.

scholarly journals 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 ◽  
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.

The Genes and Genetics of Malignant Melanoma

2002 ◽  
Vol 6 (3) ◽  
pp. 229-235 ◽  
Author(s):  
Peter Gibbs ◽  
Benjamin M. R. Brady ◽  
William A. Robinson
Keyword(s):  
High Risk ◽  
Sun Exposure ◽  
Population Based ◽  
Uv Exposure ◽  
Molecular Defect ◽  
Clinical Variables ◽  
Red Hair ◽  
Increased Risk ◽  
History Of ◽  
Self Examination

Background: Population-based studies have identified several clinical variables associated with an increased risk of developing cutaneous melanoma that include phenotype, amount of and response to sun exposure, and family history. However, these observations are of limited relevance to clinical practice as the risk associated with each factor is individually modest and the characteristics of these variables lack precision when applied to a particular individual. Objective: To review the literature regarding recent advances made in the understanding of the genes and genetics of clinical variables associated with an increased risk of melanoma. Conclusion: Variants of the MC1R (melanocortin-1 receptor) have been identified as major determinants of high-risk phenotypes, such as red hair and pale skin, and the ability to tan in response to UV exposure. Several studies also suggest that such variants may increase melanoma risk independent of their contribution to phenotype. A strong genetic basis for both nevus density and size has been demonstrated and the link between nevi and the development of MM has become better defined. Finally, germline defects in several genes involved in cell cycle regulation, namely, p16 and CDK4, have been demonstrated in many familial melanoma kindreds. This progress has introduced the prospect of genetic testing as a means of identifying a limited number of high-risk individuals who can be targeted with regular screening and education regarding UV exposure and skin self-examination. Ultimately, through rational genetic therapy targeted to correcting the underlying molecular defect, altering the natural history of melanoma development may be possible.

Abstract 500: DNA Methylation Profiling Reveals an Epithelial/Endothelial-Mesenchymal Transition-like Signature of Intima-Media Cells in the Ascending Aorta of Bicuspid Aortic Valve Patients

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Hanna M Björck ◽  
Lei Du ◽  
Valentina Paloschi ◽  
Shohreh Maleki ◽  
Silvia Pulignani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Epithelial Mesenchymal Transition ◽  
Ascending Aorta ◽  
Molecular Signature ◽  
Aortic Valves ◽  
Global Methylation ◽  
Mesenchymal Transition ◽  
Differentially Methylated Genes ◽  
Increased Risk

Introduction: Individuals with bicuspid aortic valves (BAV) are at increased risk of ascending aortic aneurysm than individuals with tricuspid aortic valves (TAV), but the underlying mechanism is not fully understood. Aberrant DNA methylation has been described in various human diseases, and we have shown that key enzymes in the methylation machinery are differentially expressed in the aortic intima-media of BAV and TAV patients. In the present study, we assessed the hypothesis that DNA methylation may play an important role during aneurysm formation in BAV. We undertook a global methylation approach to delineate biological processes associated with BAV aortopathy, using TAV as a reference. Methods: Ascending aortic biopsies were collected from 21 BAV and 24 TAV patients, with either a non-dilated or a dilated aorta, at the time of surgery. Global DNA methylation was measured in the intima-media layer using Illumina 450k Array. Gene expression was analyzed in the same samples using Affymetrix Exon Array. Results: Compared with TAV, the BAV dilated aorta was hypomethylated (P=0.031), correlating with an up-regulation of global gene expression. A total of 4913 differentially methylated regions (DMRs) were identified and Hallmark analysis of the DMR-associated genes with a fold change of 10% (n=3147) showed a gene signature of Epithelial Mesenchymal Transition (EMT) (FDR q=2.91e-29). This was further confirmed by functional annotation analysis of hypomethylated DMRs using the Genomic Regions Enrichment of Annotations Tool (Stanford University), showing association to actin filament bundle (P=7.09e-12), stress fibers (P=1.72e-11) and adherence junctions (P=2.97e-8). Interestingly, analysis of non-dilated BAV and TAV aorta revealed that genes involved in EMT were the most differentially methylated genes prior to dilatation (FDR q=1.18e-6). We further confirmed the EMT-related molecular signature by immunostaining of some key players of EMT. In conclusion, epigenetic profiling clearly revealed differential methylation between BAV and TAV aorta, particularly in EMT-related genes. Aberrant EMT in the ascending aorta prior to dilatation may constitute the basis for the increased aneurysm susceptibility in BAV patients.

scholarly journals Prognostic Value of DNA Methylation-Driven Genes in Clear Cell Renal Cell Carcinoma: A Study Based on Methylation and Transcriptome Analyses

2020 ◽  
Vol 2020 ◽  
pp. 1-14
Author(s):  
Maolin Hu ◽  
Jiangling Xie ◽  
Huiming Hou ◽  
Ming Liu ◽  
Jianye Wang
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Risk Score ◽  
Renal Cell ◽  
Methylation Level ◽  
Cox Regression ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

Background. Few previous studies have comprehensively explored the level of DNA methylation and gene expression in ccRCC. The purpose of this study was to identify the key clear cell renal cell carcinoma- (ccRCC-) related DNA methylation-driven genes (MDG) and to build a prognostic model based on the level of DNA methylation. Methods. RNA-seq transcriptome data and DNA methylation data were obtained from The Cancer Genome Atlas. Based on the MethylMix algorithm, we obtain ccRCC-related MDG. The univariate and multivariate Cox regression analyses were employed to investigate the correlation between patient overall survival and the methylation level of each MDG. Finally, a prognosis risk score was established based on a linear combination of the regression coefficient derived from the multivariate Cox regression model (β) multiplied with the methylation level of the gene. Results. 19 ccRCC-related MDG were identified. Three MDG (NCKAP1L, EVI2A, and BATF) were further screened and integrated into a prognostic risk score model, risk score=3.710∗methylation level of NCKAP1L+−3.892∗methylation level of EVI2A+−3.907∗methylation level of BATF. The risk model was independent from conventional clinical characteristics as a prognostic factor for ccRCC (HR=1.221, 95% confidence interval: 1.063–1.402, and P=0.005). The joint survival analysis showed that the gene expression and methylation levels of the prognostic genes EVI2A and BATF were significantly related with prognosis. Conclusion. This study provided an important bioinformatics foundation for in-depth studies of ccRCC DNA methylation.

Geographic Pathology of Skin Cancer

1999 ◽  
Vol 3 (3) ◽  
pp. 120-122
Author(s):  
Robert Jackson
Keyword(s):  
Squamous Cell Carcinoma ◽  
Skin Cancer ◽  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Basal Cell ◽  
Sun Exposure

Background: The development of knowledge concerning the role of sun exposure in causing skin cancer has been a gradual one. Objective: This article reviews the article by Urbach who used manikin coated with an ultraviolet dosimeter to see exactly where on the head and neck the exposure was greatest. Conclusion: Urbach showed that the areas of greatest sun exposure on his manikins corresponded with the location of 95% of squamous cell carcinoma and 66% of basal cell carcinoma. He also clearly showed the importance of scattered sky and reflected radiation.

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