An association between age and onset of premalignant lesions of the stomach was determined in this study. The findings showed that the prevalence of gastric dysplasia is higher in patients aged >60 years, whereas injuries such as gastric atrophy and intestinal metaplasia are more prevalent in patients aged 40–60 years. Similar results have been reported by other authors (22, 23), showing a direct correlation between the severity of precursor lesions of gastric malignancy and age.
The greatest age-related risk is due to genomic instability acquired over the years owing to chronic inflammation, cumulative damage by free radicals, and inefficiency of DNA repair mechanisms (24-27). On the other hand, normal gastric mucosa reportedly lacks telomerase activity, and a progressive increase in the activity of this enzyme is directly related to premalignant lesions and cancer (28). Other studies and the present investigation suggest that preneoplastic lesions represent histological changes caused by tissue aging and dysfunctional adaptive responses, thereby increasing the risk of tumors.
Regarding bacterial genotypes, the s1m1 genotype was more prevalent in the case group, whereas the s2m2 genotype was more prevalent in the control group. Similar results have been reported by Colombian and foreign authors (29-31). The role of the s1m1 genotype can be explained via different mechanisms such as the synthesis of a vacuolizing protein, which induces greater epithelial damage, development of a more persistent inflammation, and blockage in the proliferation of T lymphocytes via its arrest in the G1 or S phase of the cell cycle (32-33).
In a recent meta-analysis, 33 studies were evaluated, which overall included 2697 controls and 1446 cases with gastric cancer and precursor lesions of gastric malignancy. In that study, the s1 allele showed an increased risk of gastric atrophy (RR: 1.11 95% CI: 1.019–1.222) and intestinal metaplasia (RR: 1.41, 95% CI: 1.03–1.94). Furthermore, the m1 vacA allele was associated with intestinal metaplasia (RR: 1.57, 95% CI: 1.24–1.98); however, there was no documented increase in the risk of gastric atrophy (34). The same study showed that adjusting the model for the incidence standardized by age decreased the association of bacterial genotypes with gastric cancer. Although p-values revealed significant associations in data analysis, the lower limit of 95% CI of the s1 allele was extremely close to the null hypothesis value. In contrast, the results of the present investigation showed significant associations of the s1m1 genotype with 95% CI far from the null hypothesis both in bivariate analysis (OR: 3.82, 95% CI: 1.45–10.07) and age-adjusted multivariate logistic regression model (adjusted OR: 4.62, 95% CI: 1.7–112.53).
Similarly, the analysis of genotype distribution by diagnostic category (Table 4) helps conclude that the prevalence of the s1m1 subtype increases with the increase in the severity of premalignant lesions, whereas the opposite seems to occur for the s2m2 genotype, suggesting a proportional relationship between the severity of the lesion and bacterial genotype. These findings highlight the conceptual value of the carcinogenesis model proposed by Dr. Correa and provide an important theoretical basis for its predictive capacity for cancer risk.
The carcinogenic effect of the cagA gene product is attributable to diverse mechanisms such as the reorganization of the cytoskeleton of epithelial cells, change in cell phenotype, and activation of signaling pathways that stimulate cell proliferation (35-37). These mechanisms would partly explain a higher incidence of gastric cancer in populations wherein approximately 90% isolates are cagA+ and a lower incidence of gastric cancer wherein the prevalence of cagA+ is lower (38, 39). In the present study, the prevalence of the cagA+ genotype between case and control groups did not significantly differ, and a relationship between the cagA genotype and development of precursor lesions of gastric malignancy was not documented. These results differ from those reported in the literature (16, 40, 41). A possible explanation for this finding is related to polymorphisms of the cagA gene and
phosphorylated EPIYA motifs. For example, it has been proposed that polymorphisms of the cagA gene and phosphorylated EPIYA motifs modulate the risk of diseases such as duodenal ulcer, degree of inflammation, and risk of gastric cancer (42, 43).
The role of salt intake in the genesis of precursor lesions of gastric malignancy has been evaluated in other investigations. Although methods to quantify salt intake differ among studies, a positive relationship with gastric pathology has consistently been demonstrated (44). For example, a systematic review published by Dias-Neto et al. showed a positive association between intestinal metaplasia and salt intake. However, this association was not significant (OR: 1.53, 95% CI: 0.72–3.24) (45). Furthermore, association studies between salt intake and gastric cancer have shown positive associations that were significant when high and low salt intake were compared (OR: 2.05, 95% CI: 1.60–2.62, p < 0.005) (46). The present study showed a significant association between regular salt intake and the development of preneoplastic lesions, and intestinal metaplasia was the diagnosis that appeared to best explain this association. These findings are consistent with those reported by Chen et al. in an advanced investigation at the Department of Nariño (20).
Dietary factors such as salt intake can modulate the risk of gastric carcinogenesis by modifying host mucosal factors, regulating inflammatory response, or inducing epigenetic changes (47) The effect of salt intake on H. pylori virulence has been evaluated in microbiological, transcriptional, and proteomic studies, showing changes in bacterial morphology and a higher transcription of the cagA gene under high-salt concentration conditions (48-50). A higher carcinogenic effect related to salt intake and cagA overexpression has been demonstrated in animal models (51). In the present study, no relationship was observed between premalignant lesions of gastric cancer and the cagA genotype, but it was shown that salt intake habit increases the risk of developing precursor lesions of gastric cancer in patients with vacA cytotoxic Helicobacter genotypes (adjusted OR for salt intake: 5.19, p = 0.001). To the best of the authors’ knowledge, no studies that explore the relationship of vacA genotypes with Helicobacter and analyze the interactive effect in preneoplastic lesions have not yet been published.
Further, the present study evaluated bacterial coinfection, whose role in the development of gastric pathology is difficult to determine. For example, it has been suggested that coinfection generates a competitive growth disadvantage for the bacteria or favors growth at certain mucosal sites that would serve as niches (29). The present study shows that coinfection increases the risk of developing premalignant lesions and cancer, albeit at a much lower level than the s1m1 genotype. These results are difficult to compare with those in the literature because coinfection is associated with pathologies such as duodenal ulcer but not with the development of precursor lesions of gastric malignancy (52). This challenge is more evident in the inability to assign a particular pathological effect in cases wherein >1 bacteria are detected. However, the adjusted multivariate model showed that the regular salt intake habit increases the risk of developing preneoplastic lesions by >3 folds, suggesting that bacterial coinfection can have a primary injurious effect on gastric mucosa that could further be enhanced via dietary factors. This association of coinfection was evident in the logistic regression model and not in the bivariate model, which is consistent with the multifactorial nature of gastric cancer.
One of the limitations of the present study could be derived from the participants’ perception of the harmful effect of salt intake on human health. This perception could eventually modify their responses, thereby generating the Hawthorne effect. In an attempt to limit this effect, the questionnaire was completed before gastrointestinal endoscopy was performed, without the knowledge of the gastrointestinal endoscopic and histopathological diagnoses. Quantification of 24-h urine sodium excretion may be recommended in future studies for quantitative and precise assessment of salt intake.
The study results suggest that the s1m1 genotype is associated with the precursor lesions of gastric malignancy and that this association is strengthened with an increase in age and salt intake. On the other hand, it can be concluded that the severity of premalignant lesions of gastric malignancy is directly correlated with advanced age and cytotoxic H. pylori genotypes.