GC is one of the most common malignant tumors with a large number of new cases and deaths every year globally. Asia is a region with a high incidence of GC, accounting for about half of the total number of cases worldwide, while China is one of the countries with a high incidence of GC in Asia. Although the incidence and mortality of GC have been decreasing in recent years, they are still at the forefront of all malignant tumors. According to its anatomical location, GC can be divided into cardia and non-cardia, which have big differences in the mechanism, carcinogenesis, clinical manifestations, treatment, and prognosis. Cardia GC is similar to esophageal cancer regarding clinical characteristics, etiology, and pathology and epidemiology. Therefore, this experiment studied non-cardia GC to avoid sample clinical heterogeneity that could affect the results of the study.
The Hippo signaling pathway is a tumor inhibition pathway that was discovered in recent years, of which LATS1 and LATS2 kinase are two important components and have many important biological functions. LATS1 and LATS2 are involved in the occurrence and development of GC [15].
H. pylori infection is an important factor causing GC. Genome-wide scanning and case-control studies have confirmed that H. pylori infection is associated with individual genetic polymorphism [7]. In this study, we found that rs9552315 of LATS2 gene was associated with H. pylori infection, and the dominant model was most suitable with the lowest AIC and BIC. Compared with the TT genotype, the CC+CT genotype can reduce the risk of H. pylori infection. The other four SNPs were not associated with H. pylori infection. At present, no correlation analysis between these five SNPs and H. pylori infection has been reported, so our results need to be further verified.
Among the five selected SNPs, rs7317471 and rs9509492 were used to study the mortality of hepatocellular carcinoma (HCC) [16]. The results showed that rs7317471 was associated with mortality from HCC, and rs9509492 was considered to be an independent prognostic indicator of overall survival rate of HCC patients, while rs9509492 was not associated with the mortality of HCC. Moreover, Sebio [17] studied the association between rs558614 and rs9552315 and colorectal cancer, and the results showed that the two SNPs were not associated with the incidence risk of colorectal cancer. In this study, we analyzed the association between five SNPs of LATS1 and LATS2 genes and the risk of non-cardia GC. The results showed that LATS1 rs9393175 was associated with the risk of non-cardia GC in an overdominant model which was most suitable with the lowest AIC and BIC. Compared with the GG+AA genotype, carrying the AG genotype may reduce the risk of non-cardia GC. Therefore, the AG genotype may be a protective factor against non-cardia GC in the Baotou Han population. Besides, LATS2 rs9509492 was found to be associated with the risk of non-cardia GC. The additive genetic model is most suitable with the lowest AIC and BIC. Furthermore, no associations were found between LATS2 SNPs rs558614, rs9552315, rs7317471 and risk of non-cardia GC. To the best of our knowledge, this is the first report of associations between these five SNPs and non-cardia GC, so our experimental results need further confirmation.
Furthermore, the relationship between polymorphisms in the LATS1 and LATS2 genes and their protein expression levels were analyzed. However, no correlations were found between these five SNPs and their protein expression levels, suggesting that gene mutations at five loci of the two genes may not affect their protein expression levels. It is also possible that these five SNPs had small effects on protein expression levels that were not detected due to the small sample size of only 111 non-cardia GC tissue samples. Therefore, our experimental results need to be further confirmed by expanding the sample size.
There are several limitations to our study. Firstly, we recruited non-cardia gastric cancer cases from one hospital and selected normal controls from another two hospitals, which might not be representative of the general population and resulted in potential selection bias. Secondly, although the infection of H. pylori was correlated with non-cardia gastric cancer risk, it is difficult to measure H. pylori infection in gastric cancer patients. Gastric cancer is a multigenic disease, and patients generally develop into gastric cancer through chronic atrophic gastritis, intestinal metaplasia, low-level neoplasia, high-level neoplasia stages. H. pylori lose its colonized soil in atrophic body gastritis and disappear slowly during gastric carcinogenesis [18, 19]. Moreover, in a long disease progression, most patients were treated with the antibiotic, which resulted in the loss of H. pylori. Lack of available information on H. pylori infection status in patients with non-cardia gastric cancer limited us to adjust the potential confounding bias of this risk factor.