Different studies revealed a decreased incidences of gastric cancer globally, but it is still the most common cancer in the north and northwestern parts of Iran (2). Mazandaran, Golestan, and Ardabil Provinces are high-riskareasfor gastric cancer (2, 32). Gastric cancer is a multi-factorial disease; a high dietary intake of salt, the high prevalence of Helicobacter pylori (H. pylori) infection, smoking and gastroesophageal reflux disease are the environmental factors in the pathogenesis of this disease in Iran (2, 9). Among genetic risk factors, MUC1 (5640G>A) and PSCA (5057C>T) polymorphisms were reported in several studies earlier (33-36).
MUC1 is a large, transmembrane mucin glycoprotein expressed at the apical surface of most simple epithelia including stomach. Functions related toMUC1 are generally associated with mucins such as lubrication, hydration of cell surfaces, protection from microorganisms and degradative enzymes (37).MUC1 protein contains three different domains: short cytoplasmic, transmembrane and a large extracellular domain. The MUC1 gene in human is comprised of 7 exons that can be alternatively spliced to form different transcripts (37). At least twelve splice variants of MUC1 have been described (38).The SNP rs4072037G>A (5640G>A) located in the 5' side of the second exon determines the splicing acceptor site and produce two major MUC1 transcripts. The “G” allele determines the variant type 2 or MUC1/B and contains the first 27 bp of the 2nd exon and have 9 amino acids longer than “A”allele, which create variant type 3 or MUC1/A in the N-terminal domain (39-41).
This additional sequence is potentially changing its intracellular trafficking or subsequent processing. The impact of the 9 additional amino acids of MUC1/A on the signaling functions and intracellular localization was investigated by Imbert-Fernandez and colleagues (41). They showed that COS-7 cell line transfected by plasmid containing MUC1/A or MUC1/B had similar protein expression and plasma membrane localization. This study also showed MUC1/B and MUC1/A differs in their ability to modulate tumor necrosis α (TNFα)-induced transcription of IL-1β and IL-8, inducing the basal TGFβ expression; finally they show different inflammatory activities (41).
MUC1 could protect the gastric epithelial cells as physical barriers, so could inhibit H. pylori binding to gastric epithelial cells. The carriers of the short-short (SS) homozygous variant genotype, were at a high risk of H. pylori infection, compared to the carriers of the long-long(LL) and long-short(LS) genotypes of MUC1 variable number of tandem repeats (VNTR) (42). Miao Li and colleagues, examined the relation between H. pylori infection and three polymorphisms (rs4072037 at 1q22, rs13361707 at 5p13, and rs2274223 at 10q23) involved in the inflammatory response to the increase of gastric cancer risk. They reported that people infected by H. pylori, carrying the genotypes AA rs4072037, CT/CC rs13361707 and AG/GG rs2274223 showed an increased risk of gastric cancer(43).
Different studies (Hanze Zhang et al., 2011, J Kupcinskas et al., 2014) have shown that the G allele locus on rs4072037 was significantly associated with a decreased gastric cancer risk (44, 45).Xinyang Liu et al., 2014 suggested the G allele at rs4072037 of the MUC1 gene might have a protective rule in people from Asian countries against gastric cancer.Also, they reported that the association was more prevalent in Asian population than in Caucasians (46).
In this study, allelic comparison (G vs A), genotype comparison (GA vs AA; GG vs AA), were done and dominant model (AG+AA vs GG), recessive model (AA vs AG+GG), over-dominant model (AA+GG vs AG) was tested (47). We found that in this study, the rs4072037 AG genotype was significantly associated with the reduced risk of gastric cancer or it plays a protecting role [odds ratios (OR) = 4.296; 95 % confidence interval (CI)= 1.190-15.517, p= 0.026 for AG vs AA].
A study by Hye-Rim Song et al., 2014, with 3,245 GC cases and 700 controls suggests that the rs4072037 AG genotype was significantly associated with a reduced risk of gastric cancer [odds ratios (OR)=0.78; 95 % confidence interval (CI)=0.67–0.91 for AG vs AA]. Their data indicated a significant association between the rs4072037 G allele and reduction in risk of gastric cancer(48). Another meta-analysis by Xi Guet al., 2018, which included seventeen case–control studies) 12551 cases and 13436 controls(, suggests that the MUC1 rs4072037 polymorphism might decrease the risk of gastric cancer in four different genetic combination (G vs. A; AG vs. AA; GG vs. AA; AG+GG vs. AA). They also performed analysis using ethnicity along with G allele and found the cancer risk was decreased among Asian population but not Caucasian (49).
Similar results (including 4,220 cases and 6,384 controls) have been obtained by Duan et al, 2014 through evaluating the association between MUC1 (rs4072037) polymorphism and gastric cancer (50). Their study demonstrated that the MUC1 (rs4072037) polymorphism is associated with risk of cancer in all genetic models (G vs A; GA vs AA; GG vs AA; AG+AA vs GG; GG vs AG+AA). They suggested MUC1 (rs4072037) polymorphism had a slightly reduced gastric cancer risk among Asian population. Also, this polymorphism was significantly associated with a decreased cancer risk in all genetic models except for homozygous recessive (AA) model in Caucasian population (50).
In this study, MUC1 rs4072037 polymorphism was significantly associated with a decreased risk of cancer in all genetic models except for homozygous GG vs AA and recessive model AG+GG vs AA(G vs A: OR= 0.507, 95%CI: 0.322–0.799, p=0.003; AG vs AA: OR= 4.296, 95%CI: 1.190–15.517, p=0.026; AG+AA vs GG: OR= 3.726, 95%CI: 2.033–6.830, p=0.0001; AA+GG vs AG: (OR= 0.223, 95% CI: 0.120-0.413, p=0.0001)). Data from this case-control study indicated that four genetic models G vs A, heterozygous GA (GA vs AA), dominant (AG+AA vs GG), over-dominant model (AA+GG vs AG), were significantly associated with the decreased risk of cancer. Therefore, MUC1 rs4072037 polymorphism was associated with decreased risk of gastric cancer in northern Iran.
The Prostate Stem Cell Antigen (PSCA) is expressed in the gastric epithelium of the isthmus area. This area includes immature epithelial cells. PSCA expression increases in prostate cancer but it is reduced in gastric cancer and gastric intestinal metaplasia (51, 52). T allele carriers show lower transcriptional activity compared with the C allele carriers (5057C>T) in their gastric mucosa (31, 51). T allele carriers have 9 amino acids more than C allele carriers (natural protein of 114 amino acid residues) (53). The association of PSCA (5057C>T) variant was described in Korea and Japan population for the first time and the T allele was reported as a risk factor for gastric cancer (31). A study in Japan and Korea showed that 5057T allele plays a more significant role in diffuse gastric cancer compared with the intestinal gastric cancer (31, 54). Such results were also similar in the population of Poland and the United States (34). Other studies in Caucasian and Chinese population also confirmed that this polymorphism is a risk factor for diffuse and intestinal gastric cancer (55).
In this study, PSCA rs2294008 polymorphism was not significantly associated with a increased risk of cancer in all genetic models (T vs C (OR= 1.050, 95% CI: 0.652 –1.693, p=0.840); homozygous TT vs CC (OR= 0.903, 95% CI: 0.327 –2.492, p=0.533); heterozygous CT vs CC (OR= 1.228, 95% CI: 0.644 –2.339, p=0.533); dominant model CT+CC vs TT (OR= 1.137, 95% CI: 0.420 –3.080, p=0.800); and recessive model CC vs CT+TT (OR= 0.904, 95% CI: 0.505 –1.620, p=0.735) (Table 5). Therefore, PSCA rs2294008 polymorphism was not associated with increased risk of gastric cancer in Northern Iran.