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The Correlation Between Single Nucleotide Polymorphism Patterns and Colorectal Cancer in the Iranian Population

1 Colorectal Research Center, Shiraz University of Medical Sciences, Shiraz, IR Iran
2 Gasteroenterohepatology Research Center, Nemazee Hospital, School of Medicine, Shiraz University of Medical Sciences, Shiraz, IR Iran
3 Department of Biochemistry, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, IR Iran
*Corresponding author: Pooneh Mokarram, Department of Biochemistry, Shiraz University of Medical Sciences, P.O. Box: 1167, Shiraz, IR Iran. Tel/Fax: +98-7112303029, E-mail:
Annals of Colorectal Research. 4(3): e41527 , DOI: 10.17795/acr-41527
Article Type: Review Article; Received: Aug 15, 2016; Accepted: Aug 17, 2016; epub: Aug 24, 2016; collection: Sep 2016


Context: The incidence of colorectal cancer has significantly increased in Iran during the last decade. Accumulating evidence suggests that there is a significant correlation between genetic variations such as polymorphisms and colorectal cancer. Therefore, identification of critical polymorphisms related to colorectal cancer can contribute to find individuals at high risk of CRC.

Evidence Acquisition: The focus of this review was on published articles in English about the association between different single nucleotide polymorphisms and colorectal cancer in the Iranian population. Evidences were gathered by searching online medical databases including Google scholar, Pubmed, Scopus and Science Direct.

Conclusions: Various single nucleotide polymorphisms of critical genes indicated significant association with colorectal cancer in the Iranian population. New polymorphism markers for high risk individuals have been recognized through further investigations to reduce the incidence and mortality of colorectal cancer.

Keywords: Single Nucleotide Polymorphism; Colorectal Cancer; Iranian Population

1. Context

Colorectal cancer (CRC) is one of the most common cancers worldwide with increasing trends of incidence in Eastern countries such as Iran (1-3). Although Asian countries traditionally experience low incidence of CRC, their rapid rise in incidence was significant compared with western populations in the last decade (4). Based on the annual reports of the Cancer Institute, colorectal cancer has been identified as the third and the fifth most common cancer in Iranian females and males, respectively (5, 6). Changes in lifestyle and environmental factors along with genetic predispositions lead to this considerable surge of incidence (4). Three forms of CRC include sporadic, familial and hereditary. Overall, 25% of cases have positive family history of disease; however, CRCs frequently occurs sporadically without family history (7). There are four classified groups of sporadic CRC including; hypermutated, non-hypermutated, CpG island methylator phenotype and elevated microsatellite alterations at tetranucleotide repeats with metastatic behavior (7, 8). Two forms of hereditary CRC include familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC). Familial Adenomatous Polyposis and HNPCC occur due to inherited mutations and are observed in about 1% and 5 to 7% of CRC cases, respectively (9). It is now clear that accumulation of genetic and epigenetic alterations leads to dysregulation of the homeostatic functions and consequently neoplastic transformation of CRC (10). In this regard, molecular carcinogenesis of colorectal cancer has been extensively investigated around the world such as Iran and its pathogenesis has been far better known than any other cancer (6).

2. Evidence Acquisition

A search of Google scholar, Pubmed, Scopus and Science Direct was performed. All studies on the association between various single nucleotide polymorphisms and colorectal cancer in the Iranian population were retrieved and reviewed for this review article.

3. Results

3.1. Single Nucleotide Polymorphism (SNP)

During the sequencing process of the human genome, it became clear that the amount of genetic variation is much greater than prior estimations (11). There are different types of variations including microsatellites, variable nucleotide repeats, and complete copies of genes or regions of a chromosome. However, the most frequent sequence variation in the human genome (more than 90%) is single nucleotide polymorphisms (SNPs). Single Nucleotide Polymorphism is the stable replacement of a single base at a specific position in the genome with a frequency of about one in 1000 bp (12, 13). These SNPs may occur within coding or non-coding sequences and also intergenic regions. Although most of the SNPs are silent (synonymous) and do not modify the protein sequences, some of them change the amino acid sequence of proteins (non-synonymous) as well as gene expression and functions through influencing promoter/enhancer/silencer activity and also mRNA stability. Therefore, they may play an important role in genome evolution and also diversity among individuals such as susceptibility to disorders or drug response. Recognition and evaluation of numerous genetic variations may result in better understanding of their effects on gene function and health of individuals. Knowledge improvement in this area provides a starting point for finding new SNP markers, which can be effectively used in personalized medicine (13). In this regard, extensive studies have been conducted around the world to find the potential relationship between genetic variations and different disorders such as colorectal cancer. This review focused on published articles, which studied the correlation between different SNPs in Iranian populations and colorectal cancer incidence. Table 1 summarizes the results of 55 studies from 2007 to 2016.

Table 1.
Evaluated Single Nucleotide Polymorphisms in the Iranian Population From 2007 to 2016

3.1.1. DNA Repair Genes

The association between polymorphisms of several DNA repair genes and CRC has been investigated in Iranian populations. In this regard, Khatami et al. (14) demonstrated a significant correlation between O6-methylguanine DNA methyltransferase (MGMT) SNPs (Arg128Gln, Gly160Arg and Pro58Ser) and sporadic CRC in Tehran. Three different studies evaluated exonuclease 1 (EXO-1) SNPs. Montazer Haghighi et al. (15) indicated the correlation between Leu/Leu genotype of EXO-1 (Pro757Leu) and reduced risk of CRC. However, based on two other studies, rs1047840 and rs1635498 had no significant correlation with CRC (16, 17). The association between SNPs of MutL homolog 1 (MLH1), including rs1799777 (16) and rs1799977 (17), and CRC was significant. However, no significant relationship was observed for rs2286940 of this gene (17). X-ray repair cross-complementing protein 1 (XRCC1) (18), DNA-dependent protein kinase catalytic subunit (DNA-PKcs or XRCC7) (19) and xeroderma pigmentosum group D (XPD) (20) are three other DNA repair genes, which have been evaluated. However, the only significant gene among them was XRCC7 (rs7003908), which was investigated by Saadat et al. in Shiraz (19).

3.1.2. Immune System Related Genes

According to the results obtained from different studies, it has been demonstrated that there may be significant correlations between SNPs of several genes involved in the immune system and CRC incidence. This significant relationship was observed for Programmed cell death protein 1 gene (PD1.5 and PD1.3) (21, 22), cluster of differentiation 86 (CD86) (23), nucleotide-binding oligomerization domain-containing protein 2 (NOD-2) (24), Transforming Growth Factor beta 1 (TGF- β1) (-509 C/T) (25), Interleukin 17 (IL-17) (26) and IL-18 (-137 G/C) (27) (A A significant association was also shown between IL-16 TG genotype (rs11556218) and 1.75 fold increased risk of CRC (P = 0.005) and inverse association between Il-16 CC genotype (rs4778889) and CRC in male subjects (P = 0.045) (28). In another study in Shiraz, Mojtahedi et al. (29) indicated an association between Forkhead box P3 (FoxP3 or scurfin) C-2383T SNP and metastatic CRC. No correlation was observed for SNPs of some other genes such as, tumor necrosis factor alpha (TNF-α) (-238 G/A) (30), stromal cell-derived factor-1 (SDF-1α) (G801A) (31), IL-18 (-607C/A) (27), IL-22 (rs1179251) (34), IL-23 (rs11209026, rs1088967) (26), TGF- β1 (-800 G/A) (25), C-C chemokine receptor type 4 (CCR4) (rs2228428) (32), C-C motif chemokine 22 (CCL22) (rs4359426) (32) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (-1722T/C, -1661A/G, +49A/G and -318C/T) genotypes (33).

3.1.3. Oncogenes and Tumor Suppressor Genes

Given the critical role of the oncogenes and tumor suppressor genes, their SNPs may play an important role in various cancers, such as CRC. In this regard, SNPs of three tumor suppressor genes including tumor protein p53 (p53) (34, 35), cyclin-dependent kinase inhibitor 2A (CDKN2A or p16) (36) and Axin2 (2) were investigated in Iranian populations. Conflicting results were obtained in two separate studies for p53 (Arg72Pro). Although Doosti et al. (35) found a significant association between p53Arg/Arg genotype and susceptibility to CRC among the populations of Isfahan and Chaharmahal Va Bakhtiari; however Mojtahedi et al. (34) found that this correlation was not significant in a sample from Shiraz. No relationship was also observed between CDKN2A (rs11515) in microRNA binding site (36) and Axin2 (Pro50Ser) SNPs (2), and CRC. On the other hand, an evaluation in Tehran by Azimzadeh et al. (36) demonstrated no correlation between microRNA binding site polymorphism located in oncogene serine/threonine-protein kinase (c-RAF or RAF-1) and CRC.

3.1.4. Other Genes

Polymorphisms of some other genes have been evaluated in CRC patients and normal Iranian population. For instance, SNPs of DNA Methyltransferase 3B (DNMT3B) (37, 38), glutathione s-transferase theta-1 (GSTT1) (39), matrix metalloproteinase-1 (MMP-1) (2G/2G) (40), MMP-3 (5A/5A) (41), methylene tetrahydrofolate reductase (MTHFR) (C677T) (42, 43), Vitamin D Receptor (VDR) (ApaI) (44), multiple drug resistance 1 (MDR1) (G2677T/A) (45), epidermal growth factor (EGF) (rs6983267) (46), cyclooxygenase 2 (Cox-2) (-765G > C) (47), insulin receptor (INSR) (rs1799817) (48) and mothers against decapentaplegic homolog 7 (SMAD7) (rs4464148) (49) showed a significant correlation with CRC. However, this association was not observed for other genes such as leptin receptor (LEPR) (50), prostaglandin E2 receptor 4 (PTGER4) (36), integrin beta 4 (ITGB4) (36), cytochrome P450 2E1 (CYP2E1) (39), Insulin-like growth factor 1 (IGF1) (48, 51), insulin-like growth factor-binding protein 3 (IGFBP3) (48, 51), parathyroid hormone (PTH) (52), calcium-sensing receptor (CaSR) (52), prostaglandin-endoperoxide synthase 2 (PTGS2 or COX-2) (53) and DNMT1 (14).

3.1.5. Meta-analysis studies

There are several studies in the meta-analysis related to some of the genes mentioned above. As mentioned above, according to Iranian studies, MMP1/MMP3 (40, 41), GSTT1 (39), MTHFR (42, 43), EGF (rs6983267) (37) and TGFβ1 (25) indicated significant relationships with CRC. Similar results were obtained by other meta-analysis reports, based on 50, 23, 71 and 33 case-control studies, for MMP1/ MMP3 (54), GSTT1 (55), MTHFR (56) and EGF (57), respectively. Another meta-analysis demonstrated similar results for TGF- β1 using 4440/6785 cases/controls (58). No significant association was observed for MDR1 rs1045642 (C3435T) SNP by Samanian et al. (45) and these results were confirmed by Wang et al. (59), in a meta-analysis of 34 case-control studies. However, Khedri et al. (60) found it significant in Mashhad. Inconsistency can be also observed between the results of some studies in the meta-analysis and Iranian population. For instance, in the Iranian population ApaI and BsmI SNPs of VDR gene showed significant and non-significant correlations in CRC, respectively (44, 61). However, quite opposite results were achieved in a meta-analysis based on 23 case-control studies by Yong-Heng Bai et al. (62).

4. Conclusions

Polymorphisms of different crucial genes have been evaluated in CRC patients and the normal population. However, as illustrated in Table 1, most Iranian studies have been undertaken in Tehran and a smaller number of researches have been done in other cities like Shiraz, Isfahan, Mashhad, Chaharmahal Va Bakhtiari and Neyshabur. Given the extent of the Iranian population and possible genetic differences among them, investigations in different cities can be extremely helpful for a better understanding of the association between variations of these genes and colorectal cancer in Iran. On the other hand, due to contradictory results, further investigations are required to obtain more accurate and comprehensive results and also find new potential biomarkers for colorectal cancer.


Authors’ Contribution: Mozhdeh Zamani: primary idea, data collection, writing and design of the manuscript; Pooneh Mokarram: revision and final approval; Seyed Vahid Hosseini: revision and final approval.


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Table 1.

Evaluated Single Nucleotide Polymorphisms in the Iranian Population From 2007 to 2016

Evaluated Gene SNPs Assay Sample Size City The Relationship Between Genotypes and CRC Significant P Value OR (95% CI) Year
CTLA -4 109 patients; 190 control Tehran Non-significant for genotypes; Significant correlation between TACG haplotype (-1722T, -1661A, -318C, +49G) and CRC P = 0.009 2007 (33)
-1661A/G and +49A/G PCR-RFLP
-318C/T ARMS
MMP -1 PCR-RFLP 150 patients; 100 control Tehran Significant in smoker men P = 0.02, OD = 2.17; 95% CI: (1.23 - 3.63) 2008 (40)
MMP3 PCR-RFLP 120 patients; 60 control Tehran/Isfahan Non-significant for 5A/6A; Significant for 5A/5A genotype and CRC development and metastasis through MMP3 over-expression P > 0.05 2008 (44)
5A/5A P = 0.74, OR = 2.91; 95% CI: (0.94 - 8.98)
TNF-α-238 PCR-RFLP 51 patients; 46 control Tehran Non-significant P = 0.474 2008 (30)
-238 G/A
DNMT1 PCR/Pyrosequencing 208 patients; 213 controls Tehran Non-significant for DNMT1 P > 0.05 2009 (14)
Ile311Val, Ala147Gly
MGMT PCR/Pyrosequencing Tehran Significant association between MGMT polymorphisms and CRC: Arg128Gln; Gly160Arg P = 0.005; OR 5.53; 95%CI: (2.58 - 7.16); OR 3.04; 95%CI: (1.48 - 6.31)
Pro58Ser, Leu84Phe
Arg128Gln, Ile143Val
IL-18 Allele-specific PCR 143 patients; 312 control Shiraz Non-significant for -607C/A; Significant for -137 G/C P > 0.05 2009 (27)
TGF-β1 PCR-RFLP 134 patients; 138 control Shiraz Non-significant for-800 G/A; Significant for -509 C/T P > 0.05 2009 (25)
-509 C/T P < 0.035
MTHFR MS-PCR 175 patients; 231 control Shiraz Significant for C677T in MSI+ CRC; Non-significant for A1289C P = 0.01, OR = 2.6; 95%CI: (1.3 - 5.3) 2010 (43)
C677T and A1298C
EXO1 PCR-RFLP 90 patients; 98 control Tehran Significant inverse association OR = 0.192; 95%CI: (0.040 - 0.921) 2010 (15)
VDR PCR-RFLP 160 patients; 180 control Tehran Significant for ApaI P = 0.014, OR = 2.25; 95%CI: (1.18 - 4.28) 2010 (44)
ApaI and Taq1
P53 Allele-specific PCR 132 patients; 163 control Shiraz Non-significant P > 0.05 2010 (34)
MLH1 PCR-RFLP 140 patients; 135 control Tehran Significant P < 0.005, OR = 6.142; 95%CI: (12.543 - 3.236) 2011 (16)
IL-16 PCR-RFLP 260 patients; 405 control Tehran Significant for rs11556218TG genotype P = 0.005, OR = 1.759; 95% CI: (1.191 - 2.598) 2011 (28)
rs4072111, rs11556218, rs4778889 Significant inverse correlation between CC genotype of rs4778889 T/C SNP and CRC in male subjects P = 0.045, OR = 1.192; 95% CI: (0.038 - 0.967)
MDR1 ARMS 60 patients; 60 control Tehran Significant for G2677T/A P < 0.05 2011 (45)
C3435T, C1236T, G2677T/A Non-significant for C3435T and C1236T P > 0.05
MDR1 PCR-RFLP 118 patients; 137 control Mashhad Significant P = 0.003, OR = 2.2 2011 (60)
DNMT3B PCR-RFLP 125 patients; 135 control Isfahan Significant through DNMT3B overexpression P = 0.001, OR = 3.993; 95% CI:(1.726 - 9.238) 2011 (37)
39179 G > T
VDR PCR-RFLP 452 patients; 452 control Tehran Non-significant P > 0.05 2011 (61)
FokI and BsmI
P53 Nested PCR- RFLP 145 patients; 140 control Isfahan/ Chaharmahal Va Bakhtiari Significant P < 0.01 2011 (35)
LEPR PCR-RFLP 173 patients; 173 control Tehran Non-significant P > 0.05 2011 (50)
PD-1 Nested PCR- RFLP 175 colon cancer patients; 200 control Shiraz Significant P = 0.024, OR = 1.74; 95% CI: (1.15 - 2.62) 2012 (12)
PD-1.5 C/T (+ 7785)
MTHFR PCR/Pyrosequencing 234 patients; 257 control Tehran Significant inverse association between MTHFR 677TT genotype with colorectal cancer, especially at high levels of folate P < 0.05 2012 (42)
microRNA -binding sites located in 5 genes: IL-16 , CDKN2A ( p16 ), RAF-1 , PTGER4 , ITGB4 PCR-RFLP 249 patients; 394 control Tehran Significant for IL-16 ( rs1131445) P = 0.004 2012 (36)
MMP3 PCR-RFLP 120 patients; 100 control Isfahan Significant P = 0.0003 2012 (41)
Stromelysin 1 5A/5A
PTGS2 (COX2) PCR-RFLP 110 patients; 120 controls Isfahan Non-significant P > 0.05 2012 (53)
2765G > C
VDR PCR-RFLP 327 patients; 327 Controls Tehran Significant with a stronger association for female subjects P = 0.016,OR = 2.09; 95% CI: (1.15 - 3.78) 2012 (63)
24817 G > A
Axin2 PCR-RFLP 110 patients; 179 controls Shiraz Non-significant P > 0.05 2012 (2)
EGF PCR-RFLP 115 patients; 120 controls Isfahan Significant for rs6983267; Non-significant for rs4444903C P = 0.001 2012 (46)
rs6983267 and rs4444903 P = 0.149
GSTM1 , GSTT1 , GSTP1 and CYP2E1 PCR/Pyrosequencing 100 patients; 100 controls Tehran Significant for GSTT1; Non-significant for GSTP1, GSTM1, CYP2E1 P < 0.0001 2012 (39)
EXO1 PCR-RFLP 118 patients; 130 control Tehran Non-significant P > 0.05 2013 (16)
rs1047840 G > A
MLH1 PCR-RFLP 219 patients; 248 controls Tehran Significant for I219V; Non-significant for IVS12-169 C > T P = 0.01 2013 (17)
I219V and IVS12 - 169 C > T P > 0.05
PD-1 PCR-RFLP 80 patients; 110 controls Shiraz Significant P = 0.015 for G/G P = 0.0004 for A/A 2013 (22)
PD-1.3 G/A
CD86 AD 150 patients; 150 controls Tehran Significant P = 0.007 2013 (23)
XPD PCR-RFLP 88 patients; 88 controls Tehran Non-significant P > 0.05 2013 (20)
EGF PCR-RFLP 30 patients; 95 controls Tehran Non-significant - 2013 (64)
EGF PCR-RFLP 220 patients; 220 controls Tehran Non-significant P > 0.05 2013 (65)
FoxP3/Scurfin PCR-RFLP 108 patients; 187 controls Shiraz Non-significant between controls and patients P > 0.05 2013 (29)
C-2383T/rs3761549 Significant association between C-2383T genotype and metastatic CRC P = 0.006 in men; P = 0.03 in women
SDF -1α PCR-RFLP 109 patients; 262 controls Shiraz Non-significant P > 0.05 2013 (31)
COX-2 PCR-RFLP 131 patients; 122 controls Tehran Significant P = 0.03 2013 (47)
-765G > C
IGF-I (rs6214) PCR-RFLP 167 patients; 277 controls Tehran Non-significant P > 0.05 2013 (51)
IGFBP -3 (rs3110697)
INSR (rs1052371)
IRS2 (rs2289046)
EXO1 PCR-RFLP 111 patients; 121 controls Tehran Non-significant P > 0.05 2013 (17)
rs1635498 (C723R)
IL-22 PCR-RFLP 166 patients; 236 controls Tehran Non-significant P > 0.05 2013 (34)
PTH (rs6256) PCR-RFLP 350 patients; 510 controls Tehran Non-significant P > 0.05 2013 (52)
CaSR (rs1801725)
XRCC1 T-ARMS 112 patients; 110 controls Neyshabur Non-significant P > 0.05 2014 (18)
Arg194Trp (rs1799782C > T)
NOD2 PCR-RFLP 88 patients; 88 controls Isfahan Significant P < 0.001, OR = 3.1; 95% CI: (1.621 - 5.930) 2014 (24)
SMAD7 TaqMan assay 109 patients; 109 control Tehran Non-significant P > 0.05 2014 (66)
CCR4 PCR-RFLP 165 patients; 150 controls Shiraz Non-significant P > 0.05 2014 (32)
C1014T (rs2228428)
C16A (rs4359426)
CDKN1A PCR-RFLP 150 patients; 150 controls Tehran Non-significant P > 0.05 2014 (67)
rs762624 and rs3176336
IL-17A PCR-RFLP 202 patients; 203 controls Shiraz Significant association between TT genotype of IL-17F and reduced risk of CRC P = 0.03,OR = 0.44; 95%CI: (0.21 - 0.94) 2015 (26)
rs2275913( G197A)
IL-17F Significant correlation between AG genotype of IL-17A and increased risk of CRC compared to AA genotype P = 0.001, OR = 3.638; 95%CI: (1.814 - 7.296)
rs763780 (T7488C)
IL-23R Non-significant for IL-23 SNPs P > 0.05
r s1088967
INS (rs689) PCR-RFLP 261 patients; 339 controls Tehran Non-significant for INS, IRS1, IRS2, IGF1, and IGFBP3 P > 0.05 2015 (48)
INSR (rs1799817)
IRS1 (rs1801278)
IRS2 (rs1805097) Significant association between TT + CT genotype and CT genotype of INSR compared with the CC genotype and increased risk of CRC among females For TT + CT genotype: P = 0.007 OR = 1.93; 95 % CI: (1.20 - 3.11);
IGF1 (rs5742612) For CT genotype: P = 0.002 OR = 2.15 95 % CI: (1.31 - 3.53)
IGFBP3 (rs2854744)
SMAD7 PCR-RFLP 234 patients; 253 controls Tehran Significant association between rs4464148 AG genotype and decreased risk of CRC; Significant for rs12953717 T allele P = 0.034, OR = 0.635; 95% CI: (0.417-0.967) 2015 (49)
rs12953717 P = 0.037, OR = 1.339; 95% CI: (1.017 - 1.764)
DNMT3B PCR-RFLP 108 patients; 185 controls Shiraz Significant for TT genotype OR = 3.3; 95% CI: (1.6-6.9) 2015 (38)
XRCC7 PCR-RFLP 166 patients; 260 controls Shiraz Significant among persons with positive family history P = 0.001,OR = 6.88; 95% CI: (2.27 - 20.8) 2016 (19)
G6721T (rs7003908)