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BACKGROUND: The banking sector is one of the job sectors that experience high stress, workload, complex interpersonal relationships, and job burnout as it involves interaction with the public and financial responsibilities, which leads to high burnout and stress. The present study was conducted to assess the prevalence of burnout and stress among bank employees and to find the associated factors. METHODS: This cross-sectional survey was conducted among 282 bank employees of Kollam district, Kerala, India. Data was collected using a self-administered questionnaire related to the socio-demographic and professional details. We used the Oldenburg Burnout Inventory (OLBI) to screen for burnout levels. Depression Anxiety Stress Scale (DASS 21) to screen for the levels of depression, anxiety, and stress among study participants. Descriptive statistics were used to summarize the data, and logistic regression was used to identify the factors associated with the levels of burnout and stress. RESULTS: Of 282 study participants, moderate to high levels of burnout were observed in 232 participants (82.2%), and 74 participants (26.2%) had mild to extremely severe levels of stress. Daily average working duration showed an association with higher levels of burnout (adjusted odds ratio [ORAdj]: 2.391; 95% confidence interval [CI]: 1.12-5.10) and stress (ORAdj: 3.37; 95% CI: 1.58-7.16). CONCLUSIONS: A high prevalence of burnout and stress was observed in the present study. The duration of working hours was associated with both burnout and stress. Therefore, regulating the working hours may help adequately manage stress and burnout, thereby improving the mental health of bank employees.
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OBJECTIVE: DNA methylation data can be used to derive mitotic indices from complex tissues. Here, we assessed if the DNA methylation-derived mitotic ageing indices are associated with oral squamous cell carcinoma (OSCC) development and recurrence-free survival (RFS). METHODS: DNA methylation-based mitotic indices (MitoticAge, TNSC and hypoSC) were derived using algorithms "MitoticAge" and "epiTOC2" for the discovery [non-malignant (n = 22), premalignant (n = 22) and OSCC (n = 68) tissues] and validation datasets (GSE87053, GSE136704 and TCGA-HNSCC). Differences in mitotic indices between non-malignant, premalignant and OSCC tissues were assessed. Finally, the association between estimated mitotic indices and RFS was evaluated in OSCCs. RESULTS: In the discovery and validation datasets, increased mitotic ageing was observed in OSCC compared to non-malignant and premalignant oral tissues. HPV-positive HNSCCs had higher mitotic index TNSC. Mitotic age index hypoSC was associated with RFS in OSCC (p = 0.011, HR 2.61, 95% CI 1.24-5.48). CONCLUSIONS: DNA methylation-derived mitotic indices are associated with OSCC development and RFS. Thus, DNA methylation-derived mitotic indices may be a valuable research tool to reliably estimate the cumulative number of stem cell divisions in malignant and non-malignant oral tissues. Future research utilizing mitotic indices for predicting clinical outcomes in OSCC is warranted.
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BACKGROUND: Gingivobuccal complex oral squamous cell carcinoma (GBC-OSCC) is an aggressive malignancy with high mortality often preceded by premalignant lesions, including leukoplakia. Previous studies have reported genomic drivers in OSCC, but much remains to be elucidated about DNA methylation patterns across different stages of oral carcinogenesis. RESULTS: There is a serious lack of biomarkers and clinical application of biomarkers for early detection and prognosis of gingivobuccal complex cancers. Hence, in search of novel biomarkers, we measured genome-wide DNA methylation in 22 normal oral tissues, 22 leukoplakia, and 74 GBC-OSCC tissue samples. Both leukoplakia and GBC-OSCC had distinct methylation profiles as compared to normal oral tissue samples. Aberrant DNA methylation increases during the different stages of oral carcinogenesis, from premalignant lesions to carcinoma. We identified 846 and 5111 differentially methylated promoters in leukoplakia and GBC-OSCC, respectively, with a sizable fraction shared between the two sets. Further, we identified potential biomarkers from integrative analysis in gingivobuccal complex cancers and validated them in an independent cohort. Integration of genome, epigenome, and transcriptome data revealed candidate genes with gene expression synergistically regulated by copy number and DNA methylation changes. Regularised Cox regression identified 32 genes associated with patient survival. In an independent set of samples, we validated eight genes (FAT1, GLDC, HOXB13, CST7, CYB5A, MLLT11, GHR, LY75) from the integrative analysis and 30 genes from previously published reports. Bisulfite pyrosequencing validated GLDC (P = 0.036), HOXB13 (P < 0.0001) promoter hypermethylation, and FAT1 (P < 0.0001) hypomethylation in GBC-OSCC compared to normal controls. CONCLUSIONS: Our findings identified methylation signatures associated with leukoplakia and gingivobuccal complex cancers. The integrative analysis in GBC-OSCC identified putative biomarkers that enhance existing knowledge of oral carcinogenesis and may potentially help in risk stratification and prognosis of GBC-OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Infecciones por Papillomavirus , Humanos , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Carcinoma de Células Escamosas/metabolismo , Metilación de ADN , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Leucoplasia/genética , Carcinogénesis/genética , Neoplasias de Cabeza y Cuello/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
BACKGROUND: Orthostatic hypotension (OH) increases the risk of falls and associated morbidity and mortality in elderly. Hence, determining the prevalence of OH and its associated factors is important, especially in understudied LMIC settings. METHODS: A community-based cross-sectional study was conducted among randomly selected 240 community-dwelling elderly from Thiruvananthapuram, Kerala. The OH symptoms were assessed by standard clinical measurements and frailty was assessed by modified Fried frailty phenotype. Logistic regression analysis was conducted to assess the factors associated with OH. RESULTS: The prevalence of OH and frailty among participants was 9.6 and 29.2 percent respectively. In the first minute, OH was associated with increased odds of falls (OR = 1.97 [95%CI = 1.05, 3.72]). Increase in number of co-morbidities (ORadj = 1.82 [95%CI = 1.36, 2.48]), number of medicines used (ORadj = 1.73 [95%CI = 1.28, 2.34]), and orthostatic intolerance (ORadj = 3.67 [95%CI = 1.13, 11.94]) increased the odds of having OH. Elderly with diabetes (ORadj = 4.81 [95%CI = 1.57, 14.77]), hypertension (ORadj = 4.97 [95%CI = 1.01, 24.46]) and cognitive impairment (ORadj = 5.01 [95%CI = 1.40, 18.51]) were at a higher odds of having OH. CONCLUSIONS: OH and frailty are prevalent in community dwelling elderly in Thiruvananthapuram district. Frailty may be a risk factor for OH in the first minute. The number of co-morbidities may be an independent risk factor for OH. Hence, elderly people with comorbidities and cognitive impairment may be actively assessed for OH to prevent falls and associated injuries.
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Fragilidad , Hipertensión , Hipotensión Ortostática , Humanos , Anciano , Hipotensión Ortostática/epidemiología , Estudios Transversales , Fragilidad/epidemiología , Fragilidad/complicaciones , Hipertensión/complicaciones , Factores de Riesgo , Prevalencia , Presión SanguíneaRESUMEN
BACKGROUND: DNA methylation in blood may reflect adverse exposures accumulated over the lifetime and could therefore provide potential improvements in the prediction of cancer risk. A substantial body of research has shown associations between epigenetic aging and risk of disease, including cancer. Here we aimed to study epigenetic measures of aging and lifestyle-related factors in association with risk of breast cancer. METHODS: Using data from four prospective case-control studies nested in three cohorts of European ancestry participants, including a total of 1,655 breast cancer cases, we calculated three methylation-based measures of lifestyle factors (body mass index [BMI], tobacco smoking and alcohol consumption) and seven measures of epigenetic aging (Horvath-based, Hannum-based, PhenoAge and GrimAge). All measures were regression-adjusted for their respective risk factors and expressed per standard deviation (SD). Odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional or unconditional logistic regression and pooled using fixed-effects meta-analysis. Subgroup analyses were conducted by age at blood draw, time from blood sample to diagnosis, oestrogen receptor-positivity status and tumour stage. RESULTS: None of the measures of epigenetic aging were associated with risk of breast cancer in the pooled analysis: Horvath 'age acceleration' (AA): OR per SD = 1.02, 95%CI: 0.95-1.10; AA-Hannum: OR = 1.03, 95%CI:0.95-1.12; PhenoAge: OR = 1.01, 95%CI: 0.94-1.09 and GrimAge: OR = 1.03, 95%CI: 0.94-1.12, in models adjusting for white blood cell proportions, body mass index, smoking and alcohol consumption. The BMI-adjusted predictor of BMI was associated with breast cancer risk, OR per SD = 1.09, 95%CI: 1.01-1.17. The results for the alcohol and smoking methylation-based predictors were consistent with a null association. Risk did not appear to substantially vary by age at blood draw, time to diagnosis or tumour characteristics. CONCLUSION: We found no evidence that methylation-based measures of aging, smoking or alcohol consumption were associated with risk of breast cancer. A methylation-based marker of BMI was associated with risk and may provide insights into the underlying associations between BMI and breast cancer.
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Neoplasias de la Mama , Envejecimiento/genética , Neoplasias de la Mama/etiología , Neoplasias de la Mama/genética , Metilación de ADN , Epigénesis Genética , Femenino , Humanos , Estilo de Vida , Estudios Prospectivos , Factores de RiesgoRESUMEN
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 <1.1×10-7), 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 <5.0×10-6). 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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Café/efectos adversos , Metilación de ADN , Epigenoma , Té/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Islas de CpG , Epigénesis Genética , Femenino , Técnicas de Silenciamiento del Gen , Estudio de Asociación del Genoma Completo , Humanos , Hígado/enzimología , Masculino , Persona de Mediana Edad , Fosfoglicerato-Deshidrogenasa/antagonistas & inhibidores , Fosfoglicerato-Deshidrogenasa/genética , Factores de RiesgoRESUMEN
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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Neoplasias de la Mama/genética , ADN Tumoral Circulante , Metilación de ADN , ADN de Neoplasias , Epigénesis Genética , Neoplasias de la Mama/sangre , Estudios de Casos y Controles , Islas de CpG , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Oportunidad Relativa , Estudios Prospectivos , Medición de Riesgo , Factores de RiesgoRESUMEN
BACKGROUND: It is well established that estrogens and other hormonal factors influence breast cancer susceptibility. We hypothesized that a woman's total lifetime estrogen exposure accumulates changes in DNA methylation, detectable in the blood, which could be used in risk assessment for breast cancer. METHODS: An estimated lifetime estrogen exposure (ELEE) model was defined using epidemiological data from EPIC-Italy (n = 31,864). An epigenome-wide association study (EWAS) of ELEE was performed using existing Illumina HumanMethylation450K Beadchip (HM450K) methylation data obtained from EPIC-Italy blood DNA samples (n = 216). A methylation index (MI) of ELEE based on 31 CpG sites was developed using HM450K data from EPIC-Italy and the Generations Study and evaluated for association with breast cancer risk in an independent dataset from the Generations Study (n = 440 incident breast cancer cases matched to 440 healthy controls) using targeted bisulfite sequencing. Lastly, a meta-analysis was conducted including three additional cohorts, consisting of 1187 case-control pairs. RESULTS: We observed an estimated 5% increase in breast cancer risk per 1-year longer ELEE (OR = 1.05, 95% CI 1.04-1.07, P = 3 × 10-12) in EPIC-Italy. The EWAS identified 694 CpG sites associated with ELEE (FDR Q < 0.05). We report a DNA methylation index (MI) associated with breast cancer risk that is validated in the Generations Study targeted bisulfite sequencing data (ORQ4_vs_Q1 = 1.77, 95% CI 1.07-2.93, P = 0.027) and in the meta-analysis (ORQ4_vs_Q1 = 1.43, 95% CI 1.05-2.00, P = 0.024); however, the correlation between the MI and ELEE was not validated across study cohorts. CONCLUSION: We have identified a blood DNA methylation signature associated with breast cancer risk in this study. Further investigation is required to confirm the interaction between estrogen exposure and DNA methylation in the blood.
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Neoplasias de la Mama/genética , Metilación de ADN , Estrógenos/efectos adversos , Estudio de Asociación del Genoma Completo/métodos , Estudios de Casos y Controles , Islas de CpG , Metilación de ADN/efectos de los fármacos , Epigénesis Genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Rheumatoid arthritis (RA) is a disease of chronic systemic inflammation (SI). In the present study, we used four datasets to explore whether methylation-derived neutrophil-to-lymphocyte ratio (mdNLR) might be a marker of SI in new onset, untreated, and treated prevalent RA cases and/or a marker of treatment response to the tumour necrosis factor inhibitor (TNFi) etanercept. mdNLR was associated with increased odds of being a new onset RA case (OR = 2.32, 95% CI = 1.95-2.80, P < 2 × 10-16) and performed better in distinguishing new onset RA cases from controls compared to covariates: age, gender, and smoking status. In untreated preclinical RA cases and controls, mdNLR at baseline was associated with diagnosis of RA in later life after adjusting for batch (OR = 4.30, 95% CI = 1.52-21.71, P = 0.029) although no association was observed before batch correction. When prevalent RA cases were treated, there was no association with mdNLR in samples before and after batch correction (OR = 0.34, 95% CI = 0.05-1.82, P = 0.23), and mdNLR was not associated with treatment response to etanercept (OR = 1.10, 95% CI = 0.75-1.68, P = 0.64). Our results indicate that SI measured by DNA methylation data is indicative of the recent onset of RA. Although preclinical RA was associated with mdNLR, there was no difference in the mean mdNLR between preclinical RA cases and controls. mdNLR was not associated with RA case status if treatment for RA has commenced, and it is not associated with treatment response. In the future, mdNLR estimates may be used as a valuable research tool to reliably estimate SI in the absence of freshly collected blood samples.
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Artritis Reumatoide/diagnóstico , Inflamación/diagnóstico , Linfocitos/patología , Neutrófilos/patología , Adolescente , Adulto , Anciano , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Biomarcadores Farmacológicos , Metilación de ADN , Conjuntos de Datos como Asunto , Etanercept/farmacología , Etanercept/uso terapéutico , Femenino , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Neutrófilos/fisiología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adulto JovenRESUMEN
OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is often associated with chronic systemic inflammation (SI). In the present study, we assessed if DNA methylation-derived SI (mdSI) indices: Neutrophil-to-Lymphocyte ratio (mdNLR) and Lymphocyte-to-Monocyte ratio (mdLMR) are associated with the presence of HNSCC and overall survival (OS). MATERIALS AND METHODS: We used two peripheral blood DNA methylation datasets: an HNSCC case-control dataset (nâ¯=â¯183) and an HNSCC survival dataset (nâ¯=â¯407) to estimate mdSI indices. We then performed multivariate regressions to test the association between mdSI indices, HNSCC development and OS. RESULTS: Multivariate logistic regression revealed that elevated mdNLR was associated with increased odds of being an HNSCC case (ORâ¯=â¯3.25, 95% CIâ¯=â¯2.14-5.34, Pâ¯=â¯4â¯×â¯10-7) while the converse was observed for mdLMR (ORâ¯=â¯0.88, 95% CIâ¯=â¯0.81-0.90, Pâ¯=â¯2â¯×â¯10-3). In the HNSCC survival dataset, HPV16-E6 seropositive HNSCC cases had an elevated mdLMR (Pâ¯=â¯9â¯×â¯10-5) and a lower mdNLR (Pâ¯=â¯0.003) compared to seronegative patients. Multivariate Cox regression in the HNSCC survival dataset revealed that lower mdLMR (HRâ¯=â¯1.96, 95% CIâ¯=â¯1.30-2.95, Pâ¯=â¯0.0013) but not lower mdNLR (HRâ¯=â¯0.68, 95% CIâ¯=â¯0.46-1.00, Pâ¯=â¯0.0501) was associated with increased risk of death. CONCLUSION: Our results indicate that mdSI estimated by DNA methylation data is associated with the presence of HNSCC and overall survival. The mdSI indices may be used as a valuable research tool to reliably estimate SI in the absence of cell-based estimates. Rigorous validation of our findings in large prospective studies is warranted in the future.
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Metilación de ADN , Neoplasias de Cabeza y Cuello/genética , Inflamación/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Adulto , Anciano , Anciano de 80 o más Años , Consumo de Bebidas Alcohólicas/epidemiología , Anticuerpos Antivirales/sangre , Biomarcadores de Tumor , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Comorbilidad , Islas de CpG , Conjuntos de Datos como Asunto/estadística & datos numéricos , Femenino , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/virología , Papillomavirus Humano 16/inmunología , Papillomavirus Humano 16/aislamiento & purificación , Humanos , Estimación de Kaplan-Meier , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Proteínas Oncogénicas Virales/inmunología , Infecciones por Papillomavirus/sangre , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/mortalidad , Modelos de Riesgos Proporcionales , Proteínas Represoras/inmunología , Fumar/epidemiología , Carcinoma de Células Escamosas de Cabeza y Cuello/sangre , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/virologíaRESUMEN
Background: Methylation measures quantified by microarray techniques can be affected by systematic variation due to the technical processing of samples, which may compromise the accuracy of the measurement process and contribute to bias the estimate of the association under investigation. The quantification of the contribution of the systematic source of variation is challenging in datasets characterized by hundreds of thousands of features.In this study, we introduce a method previously developed for the analysis of metabolomics data to evaluate the performance of existing normalizing techniques to correct for unwanted variation. Illumina Infinium HumanMethylation450K was used to acquire methylation levels in over 421,000 CpG sites for 902 study participants of a case-control study on breast cancer nested within the EPIC cohort. The principal component partial R-square (PC-PR2) analysis was used to identify and quantify the variability attributable to potential systematic sources of variation. Three correcting techniques, namely ComBat, surrogate variables analysis (SVA) and a linear regression model to compute residuals were applied. The impact of each correcting method on the association between smoking status and DNA methylation levels was evaluated, and results were compared with findings from a large meta-analysis. Results: A sizeable proportion of systematic variability due to variables expressing 'batch' and 'sample position' within 'chip' was identified, with values of the partial R2 statistics equal to 9.5 and 11.4% of total variation, respectively. After application of ComBat or the residuals' methods, the contribution was 1.3 and 0.2%, respectively. The SVA technique resulted in a reduced variability due to 'batch' (1.3%) and 'sample position' (0.6%), and in a diminished variability attributable to 'chip' within a batch (0.9%). After ComBat or the residuals' corrections, a larger number of significant sites (k = 600 and k = 427, respectively) were associated to smoking status than the SVA correction (k = 96). Conclusions: The three correction methods removed systematic variation in DNA methylation data, as assessed by the PC-PR2, which lent itself as a useful tool to explore variability in large dimension data. SVA produced more conservative findings than ComBat in the association between smoking and DNA methylation.
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Neoplasias de la Mama/genética , Biología Computacional/métodos , Metilación de ADN , Estudios de Casos y Controles , Islas de CpG , Epigénesis Genética , Femenino , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Análisis de Componente PrincipalRESUMEN
The interaction between the (epi)genetic makeup of an individual and his/her environmental exposure record (exposome) is accepted as a determinant factor for a significant proportion of human malignancies. Recent evidence has highlighted the key role of epigenetic mechanisms in mediating gene-environment interactions and translating exposures into tumorigenesis. There is also growing evidence that epigenetic changes may be risk factor-specific ("fingerprints") that should prove instrumental in the discovery of new biomarkers in cancer. Here, we review the state of the science of epigenetics associated with environmental stimuli and cancer risk, highlighting key developments in the field. Critical knowledge gaps and research needs are discussed and advances in epigenomics that may help in understanding the functional relevance of epigenetic alterations. Key elements required for causality inferences linking epigenetic changes to exposure and cancer are discussed and how these alterations can be incorporated in carcinogen evaluation and in understanding mechanisms underlying epigenome deregulation by the environment.
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Exposición a Riesgos Ambientales/efectos adversos , Epigénesis Genética , Epigenómica , Interacción Gen-Ambiente , Neoplasias/etiología , Animales , Metilación de ADN , Humanos , Neoplasias/patología , Factores de RiesgoRESUMEN
Context: Even though the majority of well-differentiated thyroid carcinoma (WDTC) is indolent, a number of cases display an aggressive behavior. Cumulative evidence suggests that the deregulation of DNA methylation has the potential to point out molecular markers associated with worse prognosis. Objective: To identify a prognostic epigenetic signature in thyroid cancer. Design: Genome-wide DNA methylation assays (450k platform, Illumina) were performed in a cohort of 50 nonneoplastic thyroid tissues (NTs), 17 benign thyroid lesions (BTLs), and 74 thyroid carcinomas (60 papillary, 8 follicular, 2 Hürthle cell, 1 poorly differentiated, and 3 anaplastic). A prognostic classifier for WDTC was developed via diagonal linear discriminant analysis. The results were compared with The Cancer Genome Atlas (TCGA) database. Results: A specific epigenetic profile was detected according to each histological subtype. BTLs and follicular carcinomas showed a greater number of methylated CpG in comparison with NTs, whereas hypomethylation was predominant in papillary and undifferentiated carcinomas. A prognostic classifier based on 21 DNA methylation probes was able to predict poor outcome in patients with WDTC (sensitivity 63%, specificity 92% for internal data; sensitivity 64%, specificity 88% for TCGA data). High-risk score based on the classifier was considered an independent factor of poor outcome (Cox regression, P < 0.001). Conclusions: The methylation profile of thyroid lesions exhibited a specific signature according to the histological subtype. A meaningful algorithm composed of 21 probes was capable of predicting the recurrence in WDTC.
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Adenocarcinoma Folicular/genética , Carcinoma Papilar/genética , Epigénesis Genética , Neoplasias de la Tiroides/genética , Transcriptoma , Adenocarcinoma Folicular/patología , Adulto , Carcinoma Papilar/patología , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo/métodos , Humanos , Masculino , Análisis por Micromatrices , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Neoplasias de la Tiroides/patologíaRESUMEN
BACKGROUND: Papillary thyroid carcinoma (PTC) is a common endocrine neoplasm with a recent increase in incidence in many countries. Although PTC has been explored by gene expression and DNA methylation studies, the regulatory mechanisms of the methylation on the gene expression was poorly clarified. In this study, DNA methylation profile (Illumina HumanMethylation 450K) of 41 PTC paired with non-neoplastic adjacent tissues (NT) was carried out to identify and contribute to the elucidation of the role of novel genic and intergenic regions beyond those described in the promoter and CpG islands (CGI). An integrative and cross-validation analysis were performed aiming to identify molecular drivers and pathways that are PTC-related. RESULTS: The comparisons between PTC and NT revealed 4995 methylated probes (88% hypomethylated in PTC) and 1446 differentially expressed transcripts cross-validated by the The Cancer Genome Atlas data. The majority of these probes was found in non-promoters regions, distant from CGI and enriched by enhancers. The integrative analysis between gene expression and DNA methylation revealed 185 and 38 genes (mainly in the promoter and body regions, respectively) with negative and positive correlation, respectively. Genes showing negative correlation underlined FGF and retinoic acid signaling as critical canonical pathways disrupted by DNA methylation in PTC. BRAF mutation was detected in 68% (28 of 41) of the tumors, which presented a higher level of demethylation (95% hypomethylated probes) compared with BRAF wild-type tumors. A similar integrative analysis uncovered 40 of 254 differentially expressed genes, which are potentially regulated by DNA methylation in BRAFV600E-positive tumors. The methylation and expression pattern of six selected genes (ERBB3, FGF1, FGFR2, GABRB2, HMGA2, and RDH5) were confirmed as altered by pyrosequencing and RT-qPCR. CONCLUSIONS: DNA methylation loss in non-promoter, poor CGI and enhancer-enriched regions was a significant event in PTC, especially in tumors harboring BRAFV600E. In addition to the promoter region, gene body and 3'UTR methylation have also the potential to influence the gene expression levels (both, repressing and inducing). The integrative analysis revealed genes potentially regulated by DNA methylation pointing out potential drivers and biomarkers related to PTC development.
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Carcinoma Papilar/genética , Metilación de ADN , Perfilación de la Expresión Génica/métodos , Redes Reguladoras de Genes , Análisis de Secuencia por Matrices de Oligonucleótidos/métodos , Neoplasias de la Tiroides/genética , Regiones no Traducidas 3' , Adulto , Anciano , Simulación por Computador , Islas de CpG , Elementos de Facilitación Genéticos , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Mutación , Regiones Promotoras Genéticas , Transducción de Señal , Cáncer Papilar Tiroideo , Adulto JovenRESUMEN
We present an integrative genome-wide analysis that can be used to predict the risk of progression from leukoplakia to oral squamous cell carcinoma (OSCC) arising in the gingivobuccal complex (GBC). We find that the genomic and transcriptomic profiles of leukoplakia resemble those observed in later stages of OSCC and that several changes are associated with this progression, including amplification of 8q24.3, deletion of 8p23.2, and dysregulation of DERL3, EIF5A2, ECT2, HOXC9, HOXC13, MAL, MFAP5 and NELL2. Comparing copy number profiles of primary tumors with and without lymph-node metastasis, we identify alterations associated with metastasis, including amplifications of 3p26.3, 8q24.21, 11q22.1, 11q22.3 and deletion of 8p23.2. Integrative analysis reveals several biomarkers that have never or rarely been reported in previous OSCC studies, including amplifications of 1p36.33 (attributable to MXRA8), 3q26.31 (EIF5A2), 9p24.1 (CD274), and 12q13.2 (HOXC9 and HOXC13). Additionally, we find that amplifications of 1p36.33 and 11q22.1 are strongly correlated with poor clinical outcome. Overall, our findings delineate genomic changes that can be used in treatment management for patients with potentially malignant leukoplakia and OSCC patients with higher risk of lymph-node metastasis.
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AIM OF THE STUDY: A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. METHODS: Here, we profiled DNA methylation changes in a nested case-control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. RESULTS: We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007-1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007-1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020-1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03-1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. CONCLUSION: Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.
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Neoplasias de la Mama/genética , Metilación de ADN/genética , Epigénesis Genética/genética , Adulto , Factores de Edad , Anciano , Estudios de Casos y Controles , Metilación de ADN/fisiología , Epigenómica , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Persona de Mediana Edad , Posmenopausia/genéticaRESUMEN
BACKGROUND: DNA methylation leaves a long-term signature of smoking exposure and is one potential mechanism by which tobacco exposure predisposes to adverse health outcomes, such as cancers, osteoporosis, lung, and cardiovascular disorders. METHODS AND RESULTS: To comprehensively determine the association between cigarette smoking and DNA methylation, we conducted a meta-analysis of genome-wide DNA methylation assessed using the Illumina BeadChip 450K array on 15 907 blood-derived DNA samples from participants in 16 cohorts (including 2433 current, 6518 former, and 6956 never smokers). Comparing current versus never smokers, 2623 cytosine-phosphate-guanine sites (CpGs), annotated to 1405 genes, were statistically significantly differentially methylated at Bonferroni threshold of P<1×10-7 (18 760 CpGs at false discovery rate <0.05). Genes annotated to these CpGs were enriched for associations with several smoking-related traits in genome-wide studies including pulmonary function, cancers, inflammatory diseases, and heart disease. Comparing former versus never smokers, 185 of the CpGs that differed between current and never smokers were significant P<1×10-7 (2623 CpGs at false discovery rate <0.05), indicating a pattern of persistent altered methylation, with attenuation, after smoking cessation. Transcriptomic integration identified effects on gene expression at many differentially methylated CpGs. CONCLUSIONS: Cigarette smoking has a broad impact on genome-wide methylation that, at many loci, persists many years after smoking cessation. Many of the differentially methylated genes were novel genes with respect to biological effects of smoking and might represent therapeutic targets for prevention or treatment of tobacco-related diseases. Methylation at these sites could also serve as sensitive and stable biomarkers of lifetime exposure to tobacco smoke.
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Metilación de ADN , Epigénesis Genética , Fumar/efectos adversos , Fumar/genética , Transcriptoma , Anciano , Estudios de Casos y Controles , Islas de CpG , Femenino , Perfilación de la Expresión Génica/métodos , Marcadores Genéticos , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Leucocitos/química , Masculino , Persona de Mediana Edad , Análisis de Secuencia por Matrices de Oligonucleótidos , Fenotipo , Fumar/etnología , Cese del Hábito de Fumar , Prevención del Hábito de Fumar , Factores de TiempoRESUMEN
AIM: Epigenetic changes may occur in response to environmental stressors, and an altered epigenome pattern may represent a stable signature of environmental exposure. MATERIALS & METHODS: Here, we examined the potential of DNA methylation changes in 910 prediagnostic peripheral blood samples as a marker of exposure to tobacco smoke in a large multinational cohort. RESULTS: We identified 748 CpG sites that were differentially methylated between smokers and nonsmokers, among which we identified novel regionally clustered CpGs associated with active smoking. Importantly, we found a marked reversibility of methylation changes after smoking cessation, although specific genes remained differentially methylated up to 22 years after cessation. CONCLUSION: Our study has comprehensively cataloged the smoking-associated DNA methylation alterations and showed that these alterations are reversible after smoking cessation.
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Metilación de ADN , Fumar Tabaco/genética , Adulto , Anciano , Islas de CpG , Epigénesis Genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Secuencia de ADN , Cese del Hábito de FumarRESUMEN
Lysophosphatidic acid (LPA) is a bioactive lipid promoting cancer metastasis. LPA activates a series of six G protein-coupled receptors (LPA1-6). While blockage of LPA1in vivo inhibits breast carcinoma metastasis, down-stream genes mediating LPA-induced metastasis have not been yet identified. Herein we showed by analyzing publicly available expression data from 1488 human primary breast tumors that the gene encoding the transcription factor ZEB1 was the most correlated with LPAR1 encoding LPA1. This correlation was most prominent in basal primary breast carcinomas and restricted to cell lines of basal subtypes. Functional experiments in three different basal cell lines revealed that LPA-induced ZEB1 expression was regulated by the LPA1/Phosphatidylinositol-3-Kinase (Pi3K) axis. DNA microarray and real-time PCR analyses further demonstrated that LPA up-regulated the oncomiR miR-21 through an LPA1/Pi3K/ZEB1-dependent mechanism. Strikingly, treatment with a mirVana miR-21 inhibitor, or silencing LPA1 or ZEB1 completely blocked LPA-induced cell migration in vitro, invasion and tumor cell bone colonization in vivo, which can be restored with a mirVana miR-21 mimic. Finally, high LPAR1 expression in basal breast tumors predicted worse lung-metastasis-free survival. Collectively, our results elucidate a new molecular pathway driving LPA-induced metastasis, thus underscoring the therapeutic potential of targeting LPA1 in patients with basal breast carcinomas.