Two SNPs rs4072037 and rs2070803 of the MUC1 gene were found to be genotypic risk factors of gastric cancer. Those SNPs in combination with other socioeconomic risk factors show a significantly increased risk of gastric cancer.
Genotypic distribution of the patient group from our study was found to be similar to the one reported by Song et al. in 2014, and Zhang et al. in 2011, with AA being the most common genotype (14, 15). The results indicated the association between allele A of rs4072037 and an increased risk of gastric cancer. The risk was also elevated in the AA genotype group. Our results were supported by research done by Xu et al. in 2009 (16), by Jia et al. in 2010 (17), by Palmer et al. in 2013, and by Song et al. in 2014 (18, 19). Higher risk of cancer in patients with allele A compared to those with allele G was also pointed out by Saeki et al. in 2011 (27). On the contrary, a decreased risk of gastric cancer in patients with the G allele was found in research by Abnet et al. in 2010, and Shi et al. in 2011 (20, 21). This result was similar to multiple studies in Japanese, Korean, and Chinese population (OR ranging from 0.26 to 0.69) (15, 22, 23). The rs4072037 located in the 5’ end of the 2nd exon of MUC1 gene allows determination of the splicing point. The G allele and the A allele belong to two different variants: 2 and 3, respectively. Via mutation of amino acids in the 2nd exon, the structural differences between the two variants affect the N-terminal signal peptide, which in turn lead to a variation in function of the encoded protein. The A allele associates with gastric cancer by lowering MUC1 expression on the surface of epithelial cells lining the gastric mucosa. Mucins play a crucial role in forming protective mucous barriers on the epithelial surface of the stomach. The low expression of MUC1 may increase susceptibility to gastric cancer due to the reduced protective function of the stomach (24, 25).
As for rs2070803, in comparison with research by Fang Li et al. in 2012, despite a difference in genetic distribution, there was a similarity regarding the higher risk of gastric cancer in GG genotype when compared to AA+AG genotype OR =0.46 (95% CI = 0.32 - 0.67) (26). The quantification of association between alleles and gastric cancer risk show G compared to A with OR=2.73 but with no significant p-value. On the contrary, the research by Saeki et. al in 2011 with 3 independent data sets: Tokyo, Aichi, and Korea demonstrate a significant association between allele G and both intestinal and diffuse gastric cancer (27). This difference may be due to the limited sample size of the study. Rs2070803 on the 1q22 chromosome is an SNP located in between MUC1 and Tripartite Motif Containing 46 (TRIM46), both of which locate in a region of strong disequilibrium and are convergently transcribed (28). Numerous sources have reported the association between MUC-1 and the carcinogenesis of various tumor including gastric cancer (29, 30). However, there is no expression of TRIM46 in the gastric mucosa. This suggests rs2070803 being a tagging SNP for variants in MUC1 gene, which are associated with gastric carcinogenesis.
Regarding combinations of risk factors, old age (>60 years old) together with AA genotype of rs4072037 and GG genotype of rs 2070803 showed a notable increase in gastric cancer risks with OR=1.57 (95% CI: 1.05 – 2.34) and OR=1.5 (95% CI: 1.00 – 2.25) respectively. The majority of gastric cancer is primary and occurs in patients between the ages of 60 and 80, especially in Eastern Asia region (31, 32). Research on the Vietnamese population also reports a high incidence rate of gastric cancer in elderly people (11). The cancer growth process may involve several risk factors with different time and levels with which cells are affected. The affected cells need to be able to survive the apoptosis program in the immune system so that they can divide and multiply until tumors are formed. Due to the better immune system and shorter exposure time to most environmental risk factors that can accumulate gradually, young people tend to have a significantly lower risk of cancer in comparison to the elderly.
Gastric cancer risk was found to be increased roughly 1.8 times (p<0.05) when both genotypic (rs4072037 AA genotype or rs2070803 GG genotype) and gender (male) factors were considered. The gastric cancer incidence rate in males was reported to be approximately double that in females, particularly in countries with a high prevalence of gastric cancer. Various characteristics such as smoking, alcohol drinking, that attribute mostly to males, contribute to that fact (33). Another reason for the lower cancer rate in the female is the hormone estrogen, which was reported to have a protective effect in decreasing stomach cancer risk (34-37). A multicenter cohort study in Korea has pointed out similar results with isoflavone and phytoestrogen (38). This is further supported by several studies indicating an increased risk of gastric cancer in both genders treated with tamoxifen (an estrogen blocker) (39, 40). The result on the association between gastric cancer risk and a combination of MUC1 polymorphisms (rs4072037, rs2070803) and male gender once again showed that rs4072037 AA and rs2070803 GG are the two genotypic risk factor for stomach cancer. In our study, no notable association was found between history of alcohol abuse and gastric cancer; however, that factor together with rs4072037 AA genotype or rs2070803 GG genotype both increased risk of gastric cancer significantly with OR=2.06 (95% CI: 1.32 – 3.23) and OR= 1.98 (95% CI: 1.22 – 3.04). The effect of alcohol on gastric cancer is still in debate. Some empirical studies have suggested a carcinogenesis mechanism in which metabolic products of ethanol facilitate cancer risk factors penetration to damaged gastric mucosa, while other studies have pointed out possible protective function of ethanol due to its destructive effect on H.Pylori (40, 41). Research done on alcohol consumption rate and stomach cancer have shown divergent results, with a few authors pointing to heavy drinking of various alcohol-based beverage posing an even greater risk compared to standard alcohol (42-45).
Smoking is one of the primary risk factors that contribute to the manifestation of gastritis, atrophic gastritis, and gastric cancer in both the cardiac and non-cardiac region. Nishino et al. in 2006 have reported 1.56 times higher risk coming from patients with a history of smoking (46). According to Gonzalez, approximately 18% of gastric cancer cases can be traced back to heavy smoking. In addition, gastric cancer risk has been found to increase with long smoking time and decrease after 10 years of cessation (47). Tobacco smoke has been proven to be a mixture of many harmful chemicals relating to human gastric carcinoma (48). The smoking-related DNA adducts that bind to DNA of the gastric mucous membrane have been found in samples from smokers (49). The smoking risk factor together with AA genotype of rs4072037 and GG genotype of the rs2070803 increased risk of gastric cancer with OR= 1.72 (95% CI: 1.11 – 2.67) and OR= 1.68 (95% CI: 1.07 – 2.63) respectively. There are many studies supporting the high gastric cancer risk of patients that have a combination of genotypic risk factors (SNPs) and environmental factors (alcohol drinking/smoking). Research by Boccia et al. in 2007 has pointed out the increased gastric cancer risk in smokers with Sulfotransferase Family 1A Member 1 (SULT1A1) gene, and drinkers with CYRS2070803E1 gene (*5A allele or *6 allele) (50). Cyclooxygenase-2 (COX-2) polymorphisms together with a history of smoking play an important role in the development of gastric cardia adenocarcinoma (51). TNF-alpha-857 C/T genotypic polymorphism is an independent risk factor, and gastric cancer caused by tumor necrosis factor (TNF) gene has been argued to be related to smoking habit (52). Research by Xu et al. in 2014 has demonstrated a MUC1 mechanism, in which the inflammation signal is activated by macrophages, that contribute to the manifestation of lung cancer in patients who smoke (53).
Family history of gastric cancer is one of the major factors that double or even triple the risk of gastric cancer (54, 55). The percentage of patients who have a family history of gastric cancer in our research was 12.4%, lower than other research done in Italian (21.9%) (56), and Spanish population (17.6%) (57). A study by Dhillon et al. in 2006 on 695 cases and 629 controls in America has estimated the association between gastric cancer and family history with OR= 2.2 (95% CI: 1.5–3.3). This is further increased in individuals who have 2 or more family member diagnosed with gastric cancer, with OR=12.1 (95% CI 1.4–108) (55). Nine studies that were done in Turkey, Italia, Finland, German, and Spain also show a significant connection with OR ranging from 1.8 to 10.1 depending on different countries (58-61). Five studies on Japanese population also demonstrate the same association with OR from 1.5 to 3.5 (62, 63). Our study also show similar result (Table 3), with OR = 3.69 (95% CI: 1.78 – 7,66). The detailed mechanism of the cause and effect relationship between family history and gastric cancer is not fully understood; however, special focus has been put on genetic characteristics. In our research, patient with a family history of gastric cancer in conjunction with rs4072037 AA genotype and rs2070803 genotype elevate gastric cancer risk significantly with OR=6,47 (95% CI: 2.21 – 18,89) and OR =6,18 (95% CI: 2.11 – 18,10), respectively. This indicates the importance of family history of gastric cancer as a major risk factor for gastric cancer, especially in combination with other genotypic risk factors of rs4072037 and rs2070803. Therefore, a classification of patients according to different kinds of risk factor is necessary for management, monitoring, and prevention of gastric cancer. This could be benefited by the implementation of a complete system that focuses on the management of cancer among individuals who have a history of cancer.