Polymorphisms in mucin genes in the development of gastric cancer

Abstract

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. In areas of high prevalence, such as Japan, South Korea and China, most cases of GC are related to Helicobacter pylori (H. pylori), which involves well-characterized sequential stages, including infection, atrophic gastritis, intestinal metaplasia, dysplasia, and GC. Mucins are the most abundant high-molecular-weight glycoproteins in mucus, which is the first line of defense and plays a major role in blocking pathogenic factors. Normal gastric mucosa shows expression of MUC1, MUC5AC and MUC6 that is specific to cell type. However, the specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2. Recent studies have provided evidence that variations in these mucin genes affect many steps of GC development, such as H. pylori infection, and gastric precancerous lesions. In this review, we focus on studies of the association between polymorphisms in mucin genes and development of GC. This information should be helpful for the early detection, surveillance, and treatment of GC.

Key Words: Gastric cancer; Helicobacter pylori; Genetic polymorphism; Mucin; Risk; Association study; Atrophic gastritis

Core tip:Helicobacter pylori (H. pylori) infection is the single most important risk factor in the development of gastric cancer (GC), however the etiology of GC involves host and other environmental factors. Genetic and biological evidence highlights the important roles of variations in mucin genes in the development and progression of GC. In this review, we summarize studies of the association between polymorphisms in MUC1, MUC5AC, MUC6 and MUC2 and development of GC, which should be helpful for the early detection, surveillance, and treatment of GC.

INTRODUCTION

Although gastric cancer (GC) incidence and mortality rates are declining in most countries, it is still the fifth most common cancer and the third leading cause of cancer-related death worldwide[1]. Epidemiological studies have shown that a high intake of salt, tobacco smoking, and Helicobacter pylori (H. pylori) infection increase the risk of GC[2-4]. In areas of high prevalence of GC, such as Japan, Korea and China, most cases of GC are related to H. pylori. GC is the result of a long complex multifactorial and multistep process that involves well-characterized sequential stages. The initial lesion is inflammatory and is usually caused by H. pylori infection, which results in chronic superficial gastritis. The following pathological model of GC progression includes atrophic gastritis, intestinal metaplasia, dysplasia and GC[5,6]. H. pylori infection is the most important risk factor for GC and it was classified as a class I carcinogen by the World Health Organization in 1994, nevertheless, the etiology of GC also involves host and other environmental factors. This is demonstrated by the fact that only 1%-3% of patients with H. pylori infection develop GC[7,8]. The hypothesis that genetic susceptibility or predisposition plays an important etiological role in GC is supported by many case-control studies and genome-wide association studies (GWASs)[9-14].

H. pylori initiates colonization of the gastric mucosa by crossing the gastric mucus layer and adhering to the gastric epithelium[15]. Mucus is the first line of defense and plays a major role in blocking pathogenic factors, and mucins are the major components in mucus and are responsible for its biochemical and biophysical properties[16]. The mucin family comprises 21 members. The mucins are high-molecular-weight glycoproteins characterized by a heavily O-glycosylated tandem repeat region rich in proline, threonine and serine, which is encoded by a variable number of tandem repeats (VNTRs)[17-20]. Mucins are categorized into two subgroups according to their physiological and structural characteristics: membrane-bound, such as MUC1, and secreted, including MUC2, MUC5AC and MUC6[17]. In situ hybridization and immunohistochemistry have demonstrated the cell-type-specific expression of mucins in epithelial tissues[21,22]. Normal gastric mucosa shows cell-type-specific expression of MUC1, MUC5AC and MUC6[21-23]. Apical MUC1 is expressed in the gastric mucosa in the superficial and foveolar epithelium and mucous neck zone cells[24]. Secreted mucin MUC5AC is detected in the superficial epithelium, whereas MUC6 is found in the deep glands[25,26]. This specific pattern of MUC1, MUC5AC and MUC6 expression is changed in gastric carcinogenesis, accompanied by de novo expression of secreted MUC2[26-30]. Recent genetic and biological evidence highlights the important roles of variations in these mucin genes in the development and progression of GC. In this review, we focus on studies of the association between polymorphisms in MUC1, MUC5AC, MUC6 and MUC2 genes and development of GC (Table 1). Details of the studied single nucleotide polymorphisms (SNPs) in mucin genes are described in Table 2.

Table 1 List of association studies between polymorphisms in mucin genes and development of gastric cancer.

Gene	Ref.	Population	Disease	Study design	Sample (case/control)	Polymorphism	Association
MUC1	Vinall et al[28]	European	H. pylori related gastritis	Case–control study	57 gastritis patients	VNTR	Yes
	Carvalho et al[34]	Portuguese	GC	Case–control study	159/324	VNTR	Yes
	Silva et al[35]	Portuguese	CAG, IM	Case–control study	174 patients	VNTR	Yes
	Abnet et al[37]	Chinese	GC	GWAS	1625/2100	rs4072037	Yes
					Replication: 615/1202		No
					Combined: 2240/3302		No
	Saeki et al[39]	Japanese	DGC	Case–control study	606/1264/	rs4072037, rs2070803	Yes
		Japanese			304/1465	rs4072037, rs2070803	Yes
		South Korean			452/372	rs4072037, rs2070803	Yes
	Xu et al[40]	Chinese	GC	Case–control study	138/241	rs4072037	Yes
	Jia et al[43]	Polish	GC	Case–control study (tag SNP approach)	273/377	rs6427184	Yes
						rs4971052	Yes
						rs4276913	Yes
						rs4971088	Yes
						rs4971092	Yes
						rs4072037	Yes
	Jia et al[43]	Polish	H. pylori infection	Case–control study (tag SNP approach)	320/57	rs6427184	No
						rs4971052	No
						rs4276913	No
						rs4971088	No
						rs4971092	No
						rs4072037	No
	Zhang et al[44]	Chinese	GC	Case–control study	1681/1858	rs4072037	Yes
	Palmer et al[45]	Caucasian	GC	Case–control study	596/587	rs4072037	Yes
	Li et al[46]	Chinese	GC	Case–control study	300/300	rs2070803	Yes
	Zhang et al[47]	Chinese	Non-cardia GC	Case–control study	288/281	rs4072037	No
				(tag SNP approach)		rs2990245	No
						rs9628662	No
						rs9426886	No
	Zhang et al[47]	Chinese	H. pylori infection	Case–control study	122/159	rs4072037	No
				(tag SNP approach)		rs2990245	No
						rs9628662	No
						rs9426886	No
	Frank et al[48]	German	CAG	Case–control study	533/1054	rs4072037	No
	Marín et al[49]	Spanish	GCPLs	Case–control study	387 patients	rs3814316	No
				(tag SNP approach)		rs9426886	No
						rs1045253	No
	Sun et al[50]	Hispanic American	GC	Case–control study	132/125	rs4072037	No
	Duan et al[51]	-	GC	Meta-analysis	4220/6384	rs4072037	Yes
	Zheng et al[52]	-	GC	Meta-analysis	6580/10324	rs4072037	Yes
	Mocellin et al[42]	Asian	DGC	Meta-analysis	7279 subjects	rs2070803	Yes
MUC5AC	Jia et al[43]	Polish	GC	Case–control study (tag SNP approach)	273/377	rs1541314	No
						rs2014486	Yes
						rs2075859	No
						rs2672785	No
						rs2735733	Yes
						rs7118568	No
						rs868903	Yes
						rs4963049	No
	Jia et al[43]	Polish	H. pylori infection	Case–control study (tag SNP approach)	320/57	rs1541314	No
						rs2014486	No
						rs2075859	No
						rs2672785	No
						rs2735733	No
						rs7118568	No
						rs868903	No
						rs4963049	No
	Zhou et al[61]	Chinese	Non-cardia GC	Case–control study (tag SNP approach)	288/281	rs3793966	No
						rs7118568	No
						rs868903	No
						rs3793964	Yes
						rs3750919	No
						rs5743942	No
						rs4963062	No
						rs885454	Yes
						rs6578810	No
						rs11040869	Yes
						rs7118481	No
						rs7105198	No
	Zhou et al[62]	Chinese	H. pylori infection	Case–control study	122/159	rs3793966	No
				(tag SNP approach)		rs7118568	No
						rs868903	No
						rs3793964	No
						rs3750919	No
						rs5743942	No
						rs4963062	No
						rs885454	No
						rs6578810	No
						rs11040869	No
						rs7118481	No
						rs7105198	No
	Wang et al[63]	Chinese	GC	Case–control study	230/328	VNTR	Yes
MUC6	Nguyen et al[68]	-	H. pylori infection	Case–control study	92/68	VNTR	Yes
	Garcia et al[69]	Portuguese	GC	Case–control study	157/376	VNTR	Yes
	Kwon et al[70]	South Korean	GC	Case–control study	470/1103	VNTR	Yes
	Jia et al[43]	Polish	GC	Case–control study (tag SNP approach)	273/377	rs1128413	No
						rs4077293	No
						rs7483870	No
						rs7943115	No
						rs11602663	No
						rs11605303	No
						rs10902076	No
						rs2071174	No
						rs11245936	No
						rs10794359	No
						rs7112267	No
						rs12574439	No
						rs7119740	No
						rs11601642	No
	Jia et al[43]	Polish	H. pylori infection	Case–control study (tag SNP approach)	320/57	rs1128413	No
						rs4077293	No
						rs7483870	No
						rs7943115	No
						rs11602663	No
						rs11605303	No
						rs10902076	No
						rs2071174	No
						rs11245936	No
						rs10794359	No
						rs7112267	No
						rs12574439	No
						rs7119740	No
						rs11601642	No
	Marín et al[49]	Spanish	GCPLs	Case–control study	387 patients	rs4076950	No
				(tag SNP approach)		rs7481521	No
						rs11246384	No
						rs6597947	No
						rs9794921	No
	Frank et al[48]	German	CAG	Case–control study	533/1054	rs7481521	No
MUC2	Jeong et al[72]	South Korean	GC	Case–control study	455/457	VNTR	Yes
	Marín et al[49]	Spanish	GCPLs	Case–control study	387 patients	rs10902073	Yes
				(tag SNP approach)		rs10794281	Yes
						rs2856082	No
						rs2071174	Yes
						rs7396030	No
						rs11245936	No
						rs7944723	Yes
						rs6421972	No
						rs10794293	Yes
						rs11245954	No
						rs7480563	No
						rs7126405	No
						rs3924453	Yes
						rs4077759	Yes
	Frank et al[48]	German	CAG	Case–control study	533/1054	rs2856111	No
						rs11825977	No

CAG: Chronic atrophic gastritis; DGC: Diffuse gastric cancer; GCPLs: Gastric cancer precursor lesions; H. pylori: Helicobacter pylori; IM: Intestinal metaplasia; SNP: Single nucleotide polymorphism; GC: Gastric cancer.

Table 2 Description of the studied single nucleotide polymorphisms in mucin genes.

Gene	Chromosome	SNPs	Wild alleles	Mutated alleles	Contig position1	Location2
MUC1	1q21	rs4072037	A	G	12007689	T22T
		rs2070803	C	T	12000652	3’ flanking region
		rs6427184	A	G	11965720	3’ flanking region
		rs4971052	C	T	11968955	3’ flanking region
		rs4276913	A	G	11974610	3’ flanking region
		rs4971088	T	A	11985820	3’ flanking region
		rs4971092	T	C	11986883	3’ flanking region
		rs2990245	T	C	12043084	5’ flanking region
		rs9628662	T	G	12051963	5’ flanking region
		rs9426886	T	A	11994691	3’ flanking region
		rs3814316	C	T	11992655	3’ flanking region
		rs1045253	T	C	12046857	5’ flanking region
MUC5AC	11p15.5	rs1541314	G	A	1182293	3’ flanking region
		rs2014486	A	G	1177573	3’ flanking region
		rs2075859	C	T	1169258	3’ flanking region
		rs2672785	C	T	1165711	3’ flanking region
		rs2735733	C	T	1180410	3’ flanking region
		rs7118568	C	G	1162850	3’ flanking region
		rs868903	T	C	1161460	3’ flanking region
		rs4963049	A	G	1155197	3’ flanking region
		rs3793966	C	T	1221718	3’ flanking region
		rs3793964	C	T	1220752	3’ flanking region
		rs3750919	G	A	1211601	3’ flanking region
		rs5743942	C	T	1232798	3’ flanking region
		rs4963062	G	A	1245411	3’ flanking region
		rs885454	C	T	1162161	3’ flanking region
		rs6578810	T	G	1209349	3’ flanking region
		rs11040869	G	A	1203382	3’ flanking region
		rs7118481	G	C	1267108	3’ flanking region
		rs7105198	G	C	1086133	5’ flanking region
MUC6	11p15.5	rs1128413	C	T	950694	3’ flanking region
		rs4077293	C	T	936522	3’ flanking region
		rs7483870	C	T	916019	3’ flanking region
		rs7943115	G	A	913885	3’ flanking region
		rs11602663	C	T	960778	Intronic
		rs11605303	G	A	978110	5’ flanking region
		rs10902076	G	C	1006044	5’ flanking region
		rs2071174	C	T	1013712	5’ flanking region
		rs11245936	G	A	1026266	5’ flanking region
		rs10794359	C	T	991715	5’ flanking region
		rs7112267	C	T	996981	5’ flanking region
		rs12574439	G	C	997948	5’ flanking region
		rs7119740	C	G	1000419	5’ flanking region
		rs11601642	C	A	1002509	5’ flanking region
		rs4076950	C	T	955021	Intronic
		rs7481521	G	A	967811	V619M
		rs11246384	C	T	970448	Intronic
		rs6597947	G	T	977029	5’ flanking region
		rs9794921	G	T	979867	5’ flanking region
MUC2	11p15.5	rs10902073	C	A	1000934	5’ flanking region
		rs10794281	C	T	1003149	5’ flanking region
		rs2856082	C	G	1011562	5’ flanking region
		rs2071174	C	T	1013712	5’ flanking region
		rs7396030	C	T	1025368	Intronic
		rs11245936	G	A	1026366	G832S
		rs7944723	C	G	1039802	P1832P
		rs6421972	G	A	1042586	I2154T
		rs10794293	C	T	1045031	Intron
		rs11245954	A	G	1047170	V2459V
		rs7480563	G	A	1047741	T2524P
		rs7126405	G	A	1049388	Q2653P
		rs3924453	G	A	1051898	3’ flanking region
		rs4077759	C	T	1052068	3’ flanking region
		rs2856111	T	C	1015747	L58P
		rs11825977	A	G	1015920	V116M

¹Based on contig NT_004487.20 for MUC1 gene, and contig NT_009237.19 for MUC5AC, MUC6 and MUC2 genes;

²SNP location relative to each gene in the region. SNPs: Single nucleotide polymorphisms.

POLYMORPHISMS IN MUC1 IN THE DEVELOPMENT OF GC

MUC1 is a highly polymorphic membrane-associated mucin that is often aberrantly expressed in cancer[31]. MUC1 gene is located on chromosome 1q21 and contains a highly conserved VNTR of 20 amino acids, varying from 25 to 125 repeats, depending on the allele[32]. In recent decades, some studies were performed to investigate the potential roles of genetic variations in MUC1 in gastric carcinogenesis, but most of them were focused on the VNTRs, with inconsistent results. Costa et al[33] observed that polymorphism in the MUC1 VNTRs influenced the binding of H. pylori to gastric cells. Vinall et al[28] reported that small MUC1 VNTR alleles were correlated with H. pylori-associated gastritis in European populations. Two studies from Portugal (which has the higher risk of GC in Europe) showed that small MUC1 VNTR alleles were significantly associated with gastric carcinoma[34], as well as chronic atrophic gastritis and incomplete intestinal metaplasia, which are two well-established precursor lesions of GC[35]. However, another study from Denmark indicated that small MUC1 VNTR alleles are more frequent in the Danish population (which has the lower risk of GC in Europe) than in Portugal[36].

GWASs have recently been important in identifying potential genetic variations related to cancer susceptibility. In 2010, Abnet et al[37] conducted a GWAS in 1625 patients with GC and 2100 controls. They identified a significant SNP of rs4072037 A/G in the MUC1 gene for GC. The A allele was correlated with increased susceptibility to GC in Chinese patients during initial scanning, however, this association was not maintained in the second phase, or when the results of the two phases were combined. A GWAS on GC in Japan revealed the top 10 SNPs that were significantly related to the diffuse type of GC, which included two located in chromosome 1q22[38]. Subsequently, Saeki et al[39] performed high-density mapping to explore the susceptibility locus of GC at chromosome 1q22 and reported that two SNPs of rs2070803 and rs4072037 were significantly related to susceptibility to diffuse GC in Japan, and the results were validated in other Japanese and Korean studies. SNP rs4072037 is located in exon 2 of the MUC1 gene and controls alternative splicing at the boundary between exons 1 and 2[39-41]. This SNP affects promoter activity and disrupts the physiological function of MUC1[41,42]. The rs4072037 G allele is correlated with higher VNTRs and the A allele with lower VNTRs[41]. However, the VNTRs are unlikely to be the causal polymorphism for GC susceptibility because the TRs are not translated in normal or malignant gastric epithelial cells[39]. This suggests that the VNTRs are a tagging polymorphism for other genetic variations, such as rs4072037, related to risk of gastric carcinogenesis. It is particularly interesting that rs4072037 A is a major allele in Chinese, Japanese and Korean populations, which have a high incidence of GC, but a minor allele in Caucasians, who have a low incidence of GC. SNP rs2070803 G/A is downstream of the MUC1 and TRIM46 genes and its functional effects are unknown. MUC1 is located downstream of the TRIM46 gene. These two genes are part of a cluster, which also includes KRTCAP2, THBS3, MTX1, PKLR and HCN3, located in a region of strong linkage disequilibrium (LD) and are transcribed in opposite directions[42]. TRIM46 is not expressed in gastric mucosa[39], therefore, SNP rs2070803 might also be a tag for variants in other genes located in this LD region, such as MUC1, which are involved in gastric carcinogenesis.

In addition to GWASs, the association of MUC1 SNPs with GC has been investigated in many case-control studies using a candidate gene approach. An association study in China showed that patients with rs4072037 AA genotype had a significantly increased risk of GC[40]. Jia et al[43] conducted a population-based, case-control study in the Polish population. Each of the tested tag SNPs (including rs6427184, rs4971052, rs4276913, rs4971088, rs4971092 and rs4072037) across the MUC1 region had significant associations with increased risk of GC. This association remained significant after adjusting for multiple tests, which also demonstrated that rs4072037 AA genotype was related to increased risk of GC. However, the study showed that MUC1 tag SNPs were not associated with H. pylori infection, suggesting that the effects of MUC1 polymorphisms on risk of GC are not mediated by H. pylori infection. The association between rs4072037 A allele and increased GC risk was further replicated in Chinese and Caucasian populations[44,45]. Another study demonstrated that rs2070803 GA/AA genotypes were protective against GC, with > 50% risk reduction in Chinese individuals[46]. However, other studies have shown conflicting results. A case-control study conducted by our group showed that four tag SNPs (including rs4072037) in MUC1 were not associated with the risk of non-cardia GC, or H. pylori infection in the Han population in Northwest China[47]. Another study showed no association between rs4072037 and risk of chronic atrophic gastritis, a well-defined precursor of GC in the German population[48]. Marín et al[49] reported that three tag SNPs (rs3814316, rs9426886 and rs1045253) in MUC1 were not associated with precursor lesions of GC in a high-risk area of Spain. Another study demonstrated that rs4072037 was not associated with GC risk in Hispanic Americans[50]. To clarify the current limited and conflicting evidence, and to establish the true impact of MUC1 variations on gastric carcinogenesis, several meta-analyses have been performed. Duan et al[51] conducted an analysis of 10 case-control studies comprising 4220 cases and 6384 controls. They found that rs4072037 G allele was associated with a decreased risk of GC progression, especially in Asians. This result is consistent with the study of Zheng et al[52] of 6580 cases and 10324 controls, which suggested the involvement of MUC1 rs4072037 polymorphism in gastric carcinogenesis among Asian individuals. A further meta-analysis showed that the rare rs2070803 A allele was associated with reduced risk of diffuse-type GC[42]. All the evidence suggests that MUC1 polymorphisms, such as rs4072037, are promising biological markers for predicting GC risk, especially in Asian populations.

POLYMORPHISMS IN MUC5AC IN THE DEVELOPMENT OF GC

MUC5AC is a major secreted mucin in healthy gastric mucosa and is the major receptor for H. pylori in the human stomach. BabA and SabA adhesins on H. pylori bind to Lewis B blood group antigens on MUC5AC, facilitating colonization[53-55]. In chronic H. pylori infection, normally expressed MUC5AC and MUC5AC-producing cells may gradually decrease[56,57]. MUC5AC is located on chromosome 11p15.5[58], which often has loss of heterozygosity in patients with GC[59,60]. Studies on the association between MUC5AC polymorphisms and GC development are limited at present. Jia et al[43] investigated the relationship between eight tag SNPs of MUC5AC and GC in a Polish study. The three tag SNPs rs868903, rs2014486 and rs2735733 in the 3’ flanking region of MUC5AC were related to the risk of GC. Their minor allele homozygotes were significantly associated with increased risk of GC. However, none of the eight tested tag SNPs were associated with risk of H. pylori infection. Our group also performed a case-control study to evaluate the association of 12 tag SNPs of MUC5AC with risk of non-cardia GC in the Han population in Northwest China. We observed that three tag SNPs, rs3793964, rs11040869 and rs885454, were significantly associated with the risk of non-cardia GC. The minor allele homozygotes of rs3793964 and rs11040869, as well as the heterozygote of rs885454 had a protective effect on risk of non-cardia GC[61]. These three tag SNPs are all located in the 3’ flanking region of MUC5AC. The discrepancies between the two studies may have been due to racial differences in variant frequencies. However, few biological studies on genetic variations in MUC5AC have been reported. Similarly, our results also suggested that polymorphisms of MUC5AC gene were not associated with the risk of H. pylori infection, suggesting MUC5AC polymorphisms are involved in other processes besides bacterial binding in developing GC[62]. Wang et al[63] conducted a case-control study in the Chinese population, which reported that some variations in an upstream repetitive region of MUC5AC were associated with GC susceptibility and progression. Their findings highlight the importance of MUC5AC polymorphisms in risk of GC.

POLYMORPHISMS IN MUC6 IN THE DEVELOPMENT OF GC

The secreted mucin, MUC6, is highly expressed in normal gastric mucosa. One study has shown that MUC6 has antimicrobial properties against H. pylori. Unique glycan residues on MUC6 inhibit biosynthesis of major cell wall component cholesteryl-α-D-glucopyranoside[64]. MUC6 is aberrantly expressed in response to H. pylori infection[65], and MUC6 expression is lower in GC compared with normal mucus[66]. MUC6 is also located on chromosome 11p15.5, which is a region rich in recombination[59]. MUC1 and MUC6 have a large number of VNTRs[67]. Several studies have focused on the relationship between VNTR polymorphisms of MUC6 and GC development. In one of these, small VNTR alleles of MUC6 gene were associated with increased risk of H. pylori infection[68]. Others showed that small MUC6 VNTR alleles were more frequent in patients with GC than in healthy blood donors[69], and short rare MUC6 minisatellite 5 alleles had an effect on susceptibility to GC by regulating gene expression[70]. However, Jia et al[43] investigated the relationship between MUC6 polymorphisms and GC, using a tag SNP approach. Fourteen of the tag SNPs tested across the MUC6 region were not associated with risk of GC or H. pylori infection. The authors inferred that VNTR polymorphisms had many alleles, which might have divided the study population into several classes, thus making statistical analysis difficult. Similarly, Marín et al[49] observed that five tag SNPs in MUC6 were not associated with GC precursor lesions. Furthermore, Frank et al[48] investigated the association between polymorphism in MUC6 and the risk of chronic atrophic gastritis, using a candidate SNP approach. However, there was no association between the putative functional SNP rs7481521 (MUC6 V619M) and chronic atrophic gastritis. Further studies are needed to elucidate the roles of MUC6 polymorphisms in the gastric carcinogenesis pathway.

POLYMORPHISMS IN MUC2 IN THE DEVELOPMENT OF GC

Normal gastric mucosa shows little or no expression of MUC2. However, in intestinal metaplasia and GC, the level of MUC2 is increased[27,29,30]. MUC2 might be activated by proinflammatory cytokines expressed after H. pylori infection, leading to its overexpression[71]. MUC2 gene is clustered on chromosome 11p15.5 with MUC5AC, MUC5B and MUC6[58]. Only three studies have evaluated the relationship between MUC2 polymorphisms and development of GC. Jeong et al[72] reported that the short rare minisatellite 6 alleles of MUC2 gene are associated with GC. Marín et al[49] have investigated the association of 14 tag SNPs in MUC2 with evolution of GC precursor lesions in 387 patients with 12.8 years follow-up. According to the diagnosis at recruitment and after follow-up, the patients were divided into three groups, that is, those with no change in lesions, progression of lesions, and regression of lesions. The results indicated that three SNPs (rs10794293, rs3924453 and rs4077759) at the 3’ moiety in MUC2 were associated with a decreased risk of lesion progression. In contrast, another four SNPs (rs10902073, rs10794281, rs2071174 and rs7944723) at the 5’ moiety were significantly associated with lesion regression. The association of SNPs with GC precursor lesions was stronger in patients with H. pylori infection. However, it was also shown that functional SNP rs11825977 (V116M) in MUC2, which might influence MUC2 mRNA expression[73], as well as the potentially functional SNP rs2856111 (L58P), were not associated with the risk of chronic atrophic gastritis[48].

CONCLUSION

GC is the third leading cause of cancer mortality and a serious global problem. Many studies have tried to identify the factors responsible for GC, but the exact sequence of molecular events involved in the development of GC remains unclear. In areas of high GC prevalence, most cases are related to H. pylori infection, and GC develops through several stages, including infection, gastric atrophy, intestinal metaplasia and dysplasia. There is a lot of evidence to support the key role of mucins in development of GC. This review focused on studies of the association between polymorphisms in mucin genes and development of GC. The strength of such an association varied among the studies. The diversity in study populations and lifestyle, as well as sample size may account for this inconsistency. For example, functional SNP rs4072037 in MUC1 gene may affect the development of GC, but the effects seem to be stronger in Asian populations. Future association studies need global collaboration to expand sample size and identify more susceptibility polymorphisms. However, lifestyle factors should be taken into account to ensure accurate and significant results. Such studies will identify useful biomarkers for early detection of GC, with the potential for better disease prevention through selective treatment and surveillance of individuals harboring high-risk genetic profiles.