An association between age and onset of premalignant gastric lesions was determined in this study. The findings show that the prevalence of dysplasia is higher in patients aged >60 years whereas injuries, such as atrophy and 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 malignancy and age.
The greatest age-related risk is due to genomic instability acquired over the years owing to chronic inflammation, cumulative damage of free radicals, and the 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). Results from other studies and those of this present investigation suggest that preneoplastic lesions represent histological changes caused by tissue aging and dysfunctional adaptive responses, thereby increasing the risk for tumors.
Regarding bacterial genotypes, the s1m1 genotype was more prevalent in the case group whereas 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 division cycle (32-34)
In a recent meta-analysis, 33 studies were evaluated, which included overall 2696 controls and 1446 cases with gastric cancer and precursor lesions of malignancy. In that study, the s1 allele showed an increased risk for 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. The same study showed that adjusting the model for the incidence standardized by age decreased the association of bacterial genotypes with gastric cancer. Although the p values revealed significant associations in the data analysis, notably, the lower limits of the confidence intervals for the s1 alleles were extremely close to the null hypothesis value. In contrast, the results of the present investigation showed significant associations for the s1m1 genotype with confidence intervals far from the null hypothesis, both in the 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) also allows us to conclude that the prevalence of s1m1 subtypes increases with the increase in the severity of premalignant lesions, whereas the opposite seems to occur with s2m2 genotypes, 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 regarding 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 epithelial cell cytoskeleton, change of cellular phenotype, and activation of signaling pathways that stimulate cell proliferation (35-37). These mechanisms would partly explain the higher incidence of gastric cancer in populations where approximately 90% of isolates are cagA-positive and a lower incidence where the prevalence of positive cagA is lower (38, 39). In our study, the prevalence of the cagA-positive genotype in the cases and the reference group did not significantly differ, and a relationship between the cagA genotype and development of precursor lesions of malignancy was not documented. These results differ from those reported in the literature (16, 40, 41). A possible explanation for this finding could be related to the polymorphisms of the cagA gene and the phosphorylation state of the EPIYA motifs. For example, it has been proposed that the polymorphisms and phosphorylation status of EPIYA motifs can 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 are significant when comparing high and low salt intake (OR = 2.05; 95%CI 1.60–2.62; p < 0.005) (46). Our 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 the information published by Chen et al. in an advanced investigation in the department of Nariño (20).
Dietary factors, such as salt intake, can modulate the risk of gastric carcinogenesis by modifying host mucosal factors, regulating the 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 as well as a greater transcription of the cagA gene when salt concentrations are high (48-50). A greater carcinogenic effect related to salt intake and cagA overexpression has been demonstrated in animal models (51). In our study, no relationship was observed between premalignant lesions and cagA genotype, but it was shown that the salt intake habit increases the risk of developing precursor lesions 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 yet been published.
Further, the present investigation 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 in certain mucosal sites that would serve as niches (29). Our research shows that coinfection increases the risk of having premalignant lesions and cancer, albeit at a much lower level than the s1m1 genotypes. 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 malignancy (52). This challenge is more evident in the inability to assign a particular pathological effect in cases wherein more than one bacterium is detected. However, the adjusted multivariate model showed that the regular salt intake habit increases the risk of developing preneoplastic lesions by more than three-fold, suggesting that bacterial coinfection could have a primary injurious effect on the gastric mucosa that could further be enhanced via dietary factors. The association of coinfection was evident in the logistic regression model and not in the bivariate model, which is consistent with the gastric cancer’s multifactorial nature.
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 the responses of the participants, thereby generating a Hawthorne effect. In an attempt to limit this effect, the questionnaire was completed before gastroscopy was performed, without the knowledge of the endoscopic and histopathological diagnoses. A quantification of 24-h urine sodium excretion may be recommended in future studies for a quantitative and precise assessment of salt intake.
Our results suggest that the s1m1 H. pylori genotypes are associated with precursor lesions of malignancy and that this association is strengthened with increase in age and salt intake. On the other hand, it can be concluded that the severity of premalignant lesions is directly correlated with advanced age as well as the cytotoxic H. pylori genotypes.