Bariatric surgery-induced weight loss and associated genome-wide DNA-methylation alterations in obese individuals

Obesity is a multifactorial and chronic condition of growing universal concern. It has recently been reported that bariatric surgery is a more successful treatment for severe obesity than other noninvasive interventions, resulting in rapid significant weight loss and associated chronic disease remission. The identification of distinct epigenetic patterns in patients who are obese or have metabolic imbalances has suggested a potential role for epigenetic alterations in causal or mediating pathways in the development of obesity-related pathologies. Specific changes in the epigenome (DNA methylome), associated with metabolic disorders, can be detected in the blood. We investigated whether such epigenetic changes are reversible after weight loss using genome-wide DNA methylome analysis of blood samples from individuals with severe obesity (mean BMI ~ 45) undergoing bariatric surgery

Upper aerodigestive tract squamous cell carcinomas show distinct overall DNA methylation profiles and different molecular mechanisms behind WNT signaling disruption

SIMPLE SUMMARY: Squamous cell carcinomas of the upper aerodigestive tract are highly incident, lethal, and share the same epithelial lining of origin, risk factors and genetic alterations. However, their biological and clinical behaviors differ, having an impact on patient survival. This study aimed at identifying the main DNA methylation differences between these tumors, giving an overview of the main genomic regions affected, whether DNA methylation gains or losses are more common, the impact on gene expression and the signaling pathways affected. This knowledge will help identifying potential site-specific biomarkers as well as shedding light on whether epigenetic mechanisms explain, at least in part, the diverse behavior of upper aerodigestive tract tumors. ABSTRACT: 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

Epigenetic, Genetic and Environmental Interactions in Esophageal Squamous Cell Carcinoma from Northeast India

<div><p>Background</p><p>Esophageal squamous cell carcinoma (ESCC) develops as a result of complex epigenetic, genetic and environmental interactions. Epigenetic changes like, promoter hypermethylation of multiple tumour suppressor genes are frequent events in cancer, and certain habit-related carcinogens are thought to be capable of inducing aberrant methylation. However, the effects of environmental carcinogens depend upon the level of metabolism by carcinogen metabolizing enzymes. As such key interactions between habits related factors and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of genes are likely. However, this remains largely unexplored in ESCC. Here, we studied the interaction of various habits related factors and polymorphism of <i>GSTM1</i>/<i>GSTT1</i> genes towards inducing promoter hypermethylation of multiple tumour suppressor genes.</p><p>Methodology/Principal Findings</p><p>The study included 112 ESCC cases and 130 age and gender matched controls. Conditional logistic regression was used to calculate odds ratios (OR) and multifactor dimensionality reduction (MDR) was used to explore high order interactions. Tobacco chewing and smoking were the major individual risk factors of ESCC after adjusting for all potential confounding factors. With regards to methylation status, significantly higher methylation frequencies were observed in tobacco chewers than non chewers for all the four genes under study (p<0.01). In logistic regression analysis, betel quid chewing, alcohol consumption and null <i>GSTT1</i> genotypes imparted maximum risk for ESCC without promoter hypermethylation. Whereas, tobacco chewing, smoking and <i>GSTT1</i> null variants were the most important risk factors for ESCC with promoter hypermethylation. MDR analysis revealed two predictor models for ESCC with promoter hypermethylation (Tobacco chewing/Smoking/Betel quid chewing/<i>GSTT1</i> null) and ESCC without promoter hypermethylation (Betel quid chewing/Alcohol/<i>GSTT1</i>) with TBA of 0.69 and 0.75 respectively and CVC of 10/10 in both models.</p><p>Conclusion</p><p>Our study identified a possible interaction between tobacco consumption and carcinogen metabolizing gene polymorphisms towards modulating promoter methylation of tumour suppressor genes in ESCC.</p></div

MDR Analysis.

*<p>P-value of 1000 fold permutation test, CVC = Cross Validation Consistency, BQ = Betel Quid, Tob = Tobacco, Smk = smoking, Alc = Alcohol, Interaction models in <b>Bold</b> refers to the Best Models selected with maximum CVC, training and testing balance accuracy.</p

Interaction of betel quid and tobacco chewing, smoking, polymorphism of <i>GSTM1</i>, <i>GSTT1</i> genes with promoter methylation index of 0, 0.25–0.50 and 0.75–1.00 in ESCC.

<p>TSGs = Tumour Suppressor Genes, OR = Odds Ratio, CI = Confidence Interval, (ref) = reference group.</p><p>Adjusted for age, gender, betel quid chewing, tobacco chewing, smoking and alcohol consumption.</p

Odds Ratio of the major risk factors in esophageal squamous cell carcinoma (ESCC).

<p>OR = Odds Ratio, CI = confidence Interval, (ref) = reference group, Ca = Cases, Co = controls.</p>*<p>Adjusted for age, gender, betel quid chewing, tobacco chewing, smoking and alcohol consumption.</p

Association of habit related factors and polymorphisms of <i>GSTM1</i>, <i>GSTT1</i> genes in ESCC with and without promoter hypermethylation of <i>p16</i>, <i>DAPK, GSTP1 and BRCA1</i> genes.

<p>TSGs = Tumour Suppressor Genes, OR = Odds Ratio, CI = confidence Interval,*p</p

False Positive Report Probability for odd ratios of the best models in MDR analysis.

<p>Prior probability range = 0.25–10<b><i>⁻</i></b>⁵ to detect OR = 1.5 or 2.0; α level = observed p-value; <b><i>Bold, italics typing</i></b> = noteworthy association at 0.5 FPRP.</p

Promoter methylation profile of <i>p16, DAPK, GSTP1</i> and <i>BRCA1</i> genes of 112 ESCC patients.

<p>Each column and row represent the respective gene indicated on top and individual patients. The number indicated on the left corresponds to the patient number. Black rectangles are methylated samples, and white rectangles are unmethylated samples.</p