Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis

Crujeiras, Ana B.; Morcillo, Sonsoles; Díaz‐Lagares, Ángel; Sandoval, Juan; Castellano‐Castillo, Daniel; Torres, Esperanza; Hervás, David; Morán, Sebastian; Esteller, Manel; Macías-González, Manuel; Casanueva, Felipe F.; Tinahones, Francisco J.

doi:10.1038/s41366-018-0065-6

Cited by 41 publications

(37 citation statements)

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“…It has been shown that DNA methylation can be influenced by environmental and lifestyle factors, including smoking and unhealthy diet [14,15]. Also, alterations in DNA methylation levels have been shown to be a consequence of increased adiposity [16] and this epigenetic mechanism was proposed as a potential link between obesity and its comorbidities such as insulin resistance [17] and cancer [18,19]. Therefore, we hypothesized that weight loss resulting from bariatric surgery may lead to changes in DNA methylation profiles, potentially providing insight into molecular mechanisms underlying weight loss-induced metabolic improvement.…”

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confidence: 99%

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

et al. 2020

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Background: Severe obesity is a growing, worldwide burden and conventional therapies including radical change of diet and/or increased physical activity have limited results. Bariatric surgery has been proposed as an alternative therapy showing promising results. It leads to substantial weight loss and improvement of comorbidities such as type 2 diabetes. Increased adiposity is associated with changes in epigenetic profile, including DNA methylation. We investigated the effect of bariatric surgery on clinical profile, DNA methylation, and biological age estimated using Horvath's epigenetic clock. Results:To determine the impact of bariatric surgery and subsequent weight loss on clinical traits, a cohort of 40 severely obese individuals (BMI = 30-73 kg/m 2 ) was examined at the time of surgery and at three follow-up visits, i.e., 3, 6, and 12 months after surgery. The majority of the individuals were women (65%) and the mean age at surgery was 45.1 ± 8.1 years. We observed a significant decrease over time in BMI, fasting glucose, HbA1c, HOMA-IR, insulin, total cholesterol, triglycerides, LDL and free fatty acids levels, and a significant small increase in HDL levels (all p values < 0.05). Epigenome-wide association analysis revealed 4857 differentially methylated CpG sites 12 months after surgery (at Bonferroni-corrected p value < 1.09 × 10 −7 ). Including BMI change in the model decreased the number of significantly differentially methylated CpG sites by 51%. Gene set enrichment analysis identified overrepresentation of multiple processes including regulation of transcription, RNA metabolic, and biosynthetic processes in the cell. Bariatric surgery in severely obese patients resulted in a decrease in both biological age and epigenetic age acceleration (EAA) (mean = − 0.92, p value = 0.039). Conclusions: Our study shows that bariatric surgery leads to substantial BMI decrease and improvement of clinical outcomes observed 12 months after surgery. These changes explained part of the association between bariatric surgery and DNA methylation. We also observed a small, but significant improvement of biological age. These epigenetic changes may be modifiable by environmental lifestyle factors and could be used as potential biomarkers for obesity and in the future for obesity related comorbidities.

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Section: Introductionmentioning

confidence: 99%

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

et al. 2020

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“…However, obesity is more than an excess body-weight problem [ 8 ]. This metabolic disorder is associated with several co-diseases, such as type 2 diabetes, cardiovascular and neurological disorders, and cancer [ 9 , 10 , 11 ]. Moreover, overweight/obese subjects usually experience a strong desire to eat coupled with a lack of control over eating [ 12 ] and suffer from emotional distress and a decrease in quality of life (QoL) and sleep and sexual function [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

Effect of A Very Low-Calorie Ketogenic Diet on Food and Alcohol Cravings, Physical and Sexual Activity, Sleep Disturbances, and Quality of Life in Obese Patients

et al. 2018

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Psychological well-being and hunger and food control are two relevant factors involved in the success of weight-loss therapy in treating obesity. Thus, this study aims to evaluate food and alcohol cravings, physical and sexual activity, sleep, and life quality (QoL) in obese patients following a very low-calorie ketogenic (VLCK) diet, as well as the role of weight lost and ketosis on these parameters. A battery of psychological test was performed in twenty obese patients (12 females, 47.2 ± 10.2 year and BMI of 35.5 ± 4.4) through the course of a 4-month VLCK diet on four subsequent visits: baseline, maximum ketosis, reduced ketosis, and endpoint. Each subject acted as their own control. Relevantly, the dietary-induced changes in body composition (7.7 units of BMI lost, 18 kg of fat mass (1.2 kg of visceral fat mass)) were associated with a statistically significant improvement in food craving scores, physical activity, sleepiness, and female sexual function. Overall, these results also translated in a notable enhancement in QoL of the treated obese patients. Therefore, the rapid and sustained weight and fat mass (FM) loss induced by the VLCK diet is associated with good food control and improvements in the psychological well-being parameters in obese subjects, which could contribute to the long-term success of this therapy.

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“…In analysing results, it is important to pay more attention to the level of statistical significance. In the present study, we considered statistical significance at P-value ≤0•05, which was in accordance with most previous studies assessing specific genes (36,37) . Recently, it has been suggested that changing the default P-value threshold for statistical significance from 0•05 to 0•005 is needed for improving the reproducibility of scientific research (38) .…”

Section: Discussionmentioning

confidence: 55%

Hypomethylation of NANOG promoter in colonic mucosal cells of obese patients: a possible role of NF-κB

et al. 2018

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Obesity and particularly central obesity are the main risk factors of colon cancer. All intestinal cell populations including stem cells, their progenitors and differentiated colonocytes seem to be the origin of colorectal cancer. However, recent data support the role of differentiated cells as cancer origin especially during inflammation. Based on Yamanaka's seminal work, re-expression of few transcription factors in terminally differentiated cells creates stemness properti'es. Although these transcription factors are involved in tumorigenesis, they are epigenetically repressed in adult tissues. We proposed that obesity might regulate methylation of stemness genes in colonocytes via inflammatory signalling. Obesity-associated inflammation was analysed using Western blot analysis of phospho-IκB (inhibitor of NF-κB). Methylation-sensitive high-resolution melting analysis was performed on colonic mucosal samples of twenty obese and twenty normal-weight men to analyse promoter methylation of POU5F1 (OCT4), NANOG, MYC and CDKN2A. TNF-treated HT-29 cells were used to recapitulate the effect of NF-κB activation on stemness genes methylation. Our results showed that colonic phosphorylation of IκB, as a signal of NF-κB activation, was higher in obese subjects compared with their normal-weight counterparts. Moreover, promoter methylation of NANOG was likely to be lower in obese subjects and correlated with central obesity. HT-29 cells incubated by TNF-α showed hypomethylation of POU5F1 and MYC genes in addition to the NANOG. These results suggest that obesity-induced inflammation might be involved in the regulation of DNA methylation of oncogenic genes such as NANOG in differentiated colonocytes and thus predispose them to later oncogenic alterations.

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Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis

Abstract: The present study identifies a potential epigenome mark of obesity-related CRC that could be useful for precision medicine in the management of this disease taking into account adiposity as a relevant risk factor.

Cited by 41 publications

References 41 publications

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

The effects of bariatric surgery on clinical profile, DNA methylation, and ageing in severely obese patients

Effect of A Very Low-Calorie Ketogenic Diet on Food and Alcohol Cravings, Physical and Sexual Activity, Sleep Disturbances, and Quality of Life in Obese Patients

Hypomethylation of NANOG promoter in colonic mucosal cells of obese patients: a possible role of NF-κB

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