Stomach cancers rank fourth among global killer cancers. Its risk factors have been identified, including smoking, drinking, and Helicobacter pylori infection, as well as infection with the Epstein-Barr virus (EBV).
Infections and lifestyle factors cause the aberrant accumulation of methylated DNA, also called epigenetic alterations. These may eventually lead to the malignant transformation of the gastric cell. Non-malignant tissues have also been shown to build up such changes.
A new paper in The Lancet eBioMedicine explores whether these changes predict the future risk of stomach tumors and how epigenetic changes interact with environmental and lifestyle factors in this process.
The study from Tokyo, Japan, included people without symptoms of gastric cancer who had a stomach mucosa biopsy performed as part of a medical evaluation. The investigators examined the various factors associated with developing primary stomach cancers over time.
In addition, they compared DNA methylation status in those who developed such cancers later with those who remained cancer-free, as well as in the tumor and the surrounding mucosal tissues. They also analyzed DNA methylation data from a mucosal sample set in Singapore to validate their findings.
What did the study show?
The study included over 4,000 healthy subjects being monitored as part of the Early Disease Detection and Prevention Study at NTT Hospital, Tokyo. Among the screening procedures, esophagogastroduodenoscopy (OGDscopy) was carried out, and samples were taken.
All participants underwent gastric mucosal sampling as part of the OGDscopy, between March 2006 and November 2018. All were followed up until March 2019 with a median follow-up of ~4 years.
Alcohol consumption was classified into four grades, from less than 40 g per week (non-drinkers) to 280 g or more per week (heavy drinkers). Smoking was also categorized by pack-years (packs per day times smoking duration in years), from non-smoking at less than 1 pack-year to heavy smokers (40 or more pack-years), further classified into current or former smokers in each category.
Stomach tumors were eventually diagnosed in 77 individuals.
Lifestyle factors predict risk
Risk factors for gastric tumors included increasing age, alcohol consumption, smoking, and the presence of Helicobacter pylori in the stomach mucosa.
The risk was more than doubled with each decade of age. Heavy drinkers and light smokers were at more than twice the risk compared to non-drinkers and non-smokers, respectively. For heavy smokers, the risk was tripled compared to non-smokers.
Current heavy smokers were at the highest risk, followed by current light smokers, and then by former heavy and former light smokers, as expected. Drinking and smoking showed some overlap in the pathways in which methylation occurred but largely targeted separate sets of genes and cellular pathways.
H. pylori predicts methylation
Over half the world's population is H. pylori-positive, but its presence triggers aberrant methylation. Thus H. pylori positivity increases the risk of stomach cancer by over seven-fold, independent of other risk factors.
H. pylori positivity is associated with increased methylation in 37 marker genes in a cohort who do not drink nor smoke heavily. In contrast, H. pylori negativity was associated with normal methylation status among drinkers and with a six-gene elevation among smokers.
"These suggest that subjects with H. pylori should avoid both heavy drinking and smoking to prevent from accelerating DNA methylation in the gastric mucosa and increasing their GN risk."
Epigenetic markers in H. pylori-positive gastric mucosa samples were also correlated with a higher risk of gastric tumors and a shorter period of tumor development. These results were validated in the Singapore samples, where H. pylori positive subjects who later developed early stomach cancer had higher methylation status compared with those who did not.
Gastric atrophy predicts methylation
Specific morphological changes in the mucosa classified as gastric atrophy were associated with higher DNA methylation levels. Methylation levels were more predictive of tumor risk than the type of atrophy, despite the differences in methylation between atrophy types themselves.
Lifestyle risk factors promote methylation
Among those who were H. pylori positive, aberrant methylation predicted high and low risk groups, and similar stratification occurred among those with environmental or lifestyle risk factors.
The findings suggest that while H. pylori triggers the process of precancerous alterations in the DNA methylation status, the impact is magnified by lifestyle factors like drinking and smoking. The latter were linked to an increased frequency of precancerous mucosal morphologies.
Importantly, these are modifiable factors, showing the significance of lifestyle changes to reduce the risk of stomach cancer. For instance, smokers who quit before the next sample was collected showed significantly lower increases in DNA methylation vs those who continued to smoke.
DNA methylation independently predicts tumor risk
Individuals with H. pylori positivity, gastric atrophy, and lifestyle risk factors have a higher tumor risk. After compensating for all potential mediators such as lifestyle factors, age, H. pylori positivity, and a family history of such tumors, DNA methylation proved to pose an independent risk, doubling the odds for the occurrence of stomach cancer.
"While unfavorable lifestyles accelerated the DNA methylation accumulation, they synergistically accelerated [stomach tumor] risk in subjects with H. pylori."
What are the implications?
For stomach cancer risk models, "adding DNA methylation to the model with clinical factors improved the predictive ability." Environmental and lifestyle factors form part of an integrated model to predict the risk of stomach cancers, but this can be markedly improved by incorporating epigenetic changes as a quantitative risk marker into the model.
This could help avoid unnecessary screening of low-risk individuals while ensuring the detection of other high-risk factors like EBV that are not associated with increased methylation.
"Implementing an individualized approach to endoscopic screening, tailored to an individual's risk profile, holds the potential to achieve early detection of GN, reduce patient burden, and optimize the allocation of healthcare resources."
Further studies will be required to map the role played by differences in socioeconomic status and ethnicity, which also interact with factors driving DNA methylation.
Journal reference:
Usui, G. et al. (2023). Integrated environmental, lifestyle, and epigenetic risk prediction of primary gastric neoplasia using the longitudinally monitored cohorts. The Lancet eBioMedicine. doi: https://doi.org/10.1016/j.ebiom.2023.104844. https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(23)00410-3/fulltext.
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