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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Nov 15, 2015; 7(11): 328-337
Published online Nov 15, 2015. doi: 10.4251/wjgo.v7.i11.328
Polymorphisms in mucin genes in the development of gastric cancer
Rong Wen, Fang Gao, Cheng-Jiang Zhou, Yan-Bin Jia
Rong Wen, Fang Gao, Cheng-Jiang Zhou, Yan-Bin Jia, School of Basic Medicine, Baotou Medical College, Baotou 014060, Inner Mongolia Autonomous Region, China
Yan-Bin Jia, Inner Mongolia Institute of Digestive Diseases, the Second Affiliated Hospital of Baotou Medical College, Baotou 014030, Inner Mongolia Autonomous Region, China
Author contributions: All authors contributed to this work.
Supported by National Natural Science Foundation of China, No. 30960169 and No. 81250024; Natural Science Foundation of Inner Mongolia, No. 2011MS1103; and Inner Mongolian Committee of Science and Technology, China, No. 20110501.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this paper.
Open-Access: This article is an open-access article which selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Yan-Bin Jia, Professor, School of Basic Medicine, Baotou Medical College, 31 Jianshe Road, Donghe District, Baotou 014060, Inner Mongolia Autonomous Region, China. jyb690318@hotmail.com
Telephone: +86-472-7167832 Fax: +86-472-7167739
Received: April 25, 2015
Peer-review started: April 26, 2015
First decision: June 2, 2015
Revised: July 1, 2015
Accepted: August 30, 2015
Article in press: September 7, 2015
Published online: November 15, 2015

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.
GeneRef.PopulationDiseaseStudy designSample (case/control)PolymorphismAssociation
MUC1Vinall et al[28]EuropeanH. pylori related gastritisCase–control study57 gastritis patientsVNTRYes
Carvalho et al[34]PortugueseGCCase–control study159/324VNTRYes
Silva et al[35]PortugueseCAG, IMCase–control study174 patientsVNTRYes
Abnet et al[37]ChineseGCGWAS1625/2100rs4072037Yes
Replication: 615/1202No
Combined: 2240/3302No
Saeki et al[39]JapaneseDGCCase–control study606/1264/rs4072037, rs2070803Yes
Japanese304/1465rs4072037, rs2070803Yes
South Korean452/372rs4072037, rs2070803Yes
Xu et al[40]ChineseGCCase–control study138/241rs4072037Yes
Jia et al[43]PolishGCCase–control study (tag SNP approach)273/377rs6427184Yes
rs4971052Yes
rs4276913Yes
rs4971088Yes
rs4971092Yes
rs4072037Yes
Jia et al[43]PolishH. pylori infectionCase–control study (tag SNP approach)320/57rs6427184No
rs4971052No
rs4276913No
rs4971088No
rs4971092No
rs4072037No
Zhang et al[44]ChineseGCCase–control study1681/1858rs4072037Yes
Palmer et al[45]CaucasianGCCase–control study596/587rs4072037Yes
Li et al[46]ChineseGCCase–control study300/300rs2070803Yes
Zhang et al[47]ChineseNon-cardia GCCase–control study288/281rs4072037No
(tag SNP approach)rs2990245No
rs9628662No
rs9426886No
Zhang et al[47]ChineseH. pylori infectionCase–control study122/159rs4072037No
(tag SNP approach)rs2990245No
rs9628662No
rs9426886No
Frank et al[48]GermanCAGCase–control study533/1054rs4072037No
Marín et al[49]SpanishGCPLsCase–control study387 patientsrs3814316No
(tag SNP approach)rs9426886No
rs1045253No
Sun et al[50]Hispanic AmericanGCCase–control study132/125rs4072037No
Duan et al[51]-GCMeta-analysis4220/6384rs4072037Yes
Zheng et al[52]-GCMeta-analysis6580/10324rs4072037Yes
Mocellin et al[42]AsianDGCMeta-analysis7279 subjectsrs2070803Yes
MUC5ACJia et al[43]PolishGCCase–control study (tag SNP approach)273/377rs1541314No
rs2014486Yes
rs2075859No
rs2672785No
rs2735733Yes
rs7118568No
rs868903Yes
rs4963049No
Jia et al[43]PolishH. pylori infectionCase–control study (tag SNP approach)320/57rs1541314No
rs2014486No
rs2075859No
rs2672785No
rs2735733No
rs7118568No
rs868903No
rs4963049No
Zhou et al[61]ChineseNon-cardia GCCase–control study (tag SNP approach)288/281rs3793966No
rs7118568No
rs868903No
rs3793964Yes
rs3750919No
rs5743942No
rs4963062No
rs885454Yes
rs6578810No
rs11040869Yes
rs7118481No
rs7105198No
Zhou et al[62]ChineseH. pylori infectionCase–control study122/159rs3793966No
(tag SNP approach)rs7118568No
rs868903No
rs3793964No
rs3750919No
rs5743942No
rs4963062No
rs885454No
rs6578810No
rs11040869No
rs7118481No
rs7105198No
Wang et al[63]ChineseGCCase–control study230/328VNTRYes
MUC6Nguyen et al[68]-H. pylori infectionCase–control study92/68VNTRYes
Garcia et al[69]PortugueseGCCase–control study157/376VNTRYes
Kwon et al[70]South KoreanGCCase–control study470/1103VNTRYes
Jia et al[43]PolishGCCase–control study (tag SNP approach)273/377rs1128413No
rs4077293No
rs7483870No
rs7943115No
rs11602663No
rs11605303No
rs10902076No
rs2071174No
rs11245936No
rs10794359No
rs7112267No
rs12574439No
rs7119740No
rs11601642No
Jia et al[43]PolishH. pylori infectionCase–control study (tag SNP approach)320/57rs1128413No
rs4077293No
rs7483870No
rs7943115No
rs11602663No
rs11605303No
rs10902076No
rs2071174No
rs11245936No
rs10794359No
rs7112267No
rs12574439No
rs7119740No
rs11601642No
Marín et al[49]SpanishGCPLsCase–control study387 patientsrs4076950No
(tag SNP approach)rs7481521No
rs11246384No
rs6597947No
rs9794921No
Frank et al[48]GermanCAGCase–control study533/1054rs7481521No
MUC2Jeong et al[72]South KoreanGCCase–control study455/457VNTRYes
Marín et al[49]SpanishGCPLsCase–control study387 patientsrs10902073Yes
(tag SNP approach)rs10794281Yes
rs2856082No
rs2071174Yes
rs7396030No
rs11245936No
rs7944723Yes
rs6421972No
rs10794293Yes
rs11245954No
rs7480563No
rs7126405No
rs3924453Yes
rs4077759Yes
Frank et al[48]GermanCAGCase–control study533/1054rs2856111No
rs11825977No
Table 2 Description of the studied single nucleotide polymorphisms in mucin genes.
GeneChromosomeSNPsWild allelesMutated allelesContig position1Location2
MUC11q21rs4072037AG12007689T22T
rs2070803CT120006523’ flanking region
rs6427184AG119657203’ flanking region
rs4971052CT119689553’ flanking region
rs4276913AG119746103’ flanking region
rs4971088TA119858203’ flanking region
rs4971092TC119868833’ flanking region
rs2990245TC120430845’ flanking region
rs9628662TG120519635’ flanking region
rs9426886TA119946913’ flanking region
rs3814316CT119926553’ flanking region
rs1045253TC120468575’ flanking region
MUC5AC11p15.5rs1541314GA11822933’ flanking region
rs2014486AG11775733’ flanking region
rs2075859CT11692583’ flanking region
rs2672785CT11657113’ flanking region
rs2735733CT11804103’ flanking region
rs7118568CG11628503’ flanking region
rs868903TC11614603’ flanking region
rs4963049AG11551973’ flanking region
rs3793966CT12217183’ flanking region
rs3793964CT12207523’ flanking region
rs3750919GA12116013’ flanking region
rs5743942CT12327983’ flanking region
rs4963062GA12454113’ flanking region
rs885454CT11621613’ flanking region
rs6578810TG12093493’ flanking region
rs11040869GA12033823’ flanking region
rs7118481GC12671083’ flanking region
rs7105198GC10861335’ flanking region
MUC611p15.5rs1128413CT9506943’ flanking region
rs4077293CT9365223’ flanking region
rs7483870CT9160193’ flanking region
rs7943115GA9138853’ flanking region
rs11602663CT960778Intronic
rs11605303GA9781105’ flanking region
rs10902076GC10060445’ flanking region
rs2071174CT10137125’ flanking region
rs11245936GA10262665’ flanking region
rs10794359CT9917155’ flanking region
rs7112267CT9969815’ flanking region
rs12574439GC9979485’ flanking region
rs7119740CG10004195’ flanking region
rs11601642CA10025095’ flanking region
rs4076950CT955021Intronic
rs7481521GA967811V619M
rs11246384CT970448Intronic
rs6597947GT9770295’ flanking region
rs9794921GT9798675’ flanking region
MUC211p15.5rs10902073CA10009345’ flanking region
rs10794281CT10031495’ flanking region
rs2856082CG10115625’ flanking region
rs2071174CT10137125’ flanking region
rs7396030CT1025368Intronic
rs11245936GA1026366G832S
rs7944723CG1039802P1832P
rs6421972GA1042586I2154T
rs10794293CT1045031Intron
rs11245954AG1047170V2459V
rs7480563GA1047741T2524P
rs7126405GA1049388Q2653P
rs3924453GA10518983’ flanking region
rs4077759CT10520683’ flanking region
rs2856111TC1015747L58P
rs11825977AG1015920V116M
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.

Footnotes

P- Reviewer: Chiurillo MA S- Editor: Ma YJ L- Editor: A E- Editor: Jiao XK

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