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Erschienen in: Environmental Health and Preventive Medicine 1/2018

Open Access 01.12.2018 | Research article

The association between IGF1 gene rs1520220 polymorphism and cancer susceptibility: a meta-analysis based on 12,884 cases and 58,304 controls

verfasst von: Gui-Ping Xu, Wei-Xian Chen, Wen-Yue Xie, Li-Fang Wu

Erschienen in: Environmental Health and Preventive Medicine | Ausgabe 1/2018

Abstract

Background

The rs1520220 polymorphism in the insulin-like growth factor 1 (IGF1) gene has been reported to affect cancer susceptibly in several studies. However, the results of the relevant studies are inconsistent. We conduct a current meta-analysis to investigate the association between rs1520220 and cancer susceptibly.

Methods

Three databases (PubMed, Embase, and Web of Science) were searched for studies regarding the relationship between rs1520220 and cancer susceptibly. Odds ratios (ORs) and the related 95% confidence intervals (CIs) were employed to assess the strength of the associations. A stratified analysis was performed according to cancer type, ethnicity, and quality score, and when results were obtained from no fewer than two studies, these results were pooled.

Results

There was no positive association between rs1520220 and overall cancer risk. However, the analysis stratified by ethnicity revealed that rs1520220 significantly increased cancer susceptibility in Asian populations (allele model OR = 1.10, 95%Cl = 1.00–1.21, p = 0.040; homozygote model OR = 1.22, 95%Cl = 1.01–1.47, p = 0.040; dominant model OR = 1.19, 95%Cl = 1.01–1.39, p = 0.033). No significantly association was detected in Caucasian populations. The analysis stratified by cancer type suggested that rs1520220 was not associated with susceptibility to breast cancer.

Conclusions

The results of our meta-analysis demonstrate that the role of IGF1 rs1520220 in cancer susceptibility varies by ethnicity and cancer type and that rs1520220 increases cancer susceptibility in Asian populations.
Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s12199-018-0727-y) contains supplementary material, which is available to authorized users.
Abkürzungen
3′-UTR
three prime untranslated region
ALL
Acute lymphoblastic leukemia
CI
Confidence interval
EAC
Esophageal adenocarcinoma
HB
Hospital-based
HNC
Head and neck cancer
HWE
Hardy-Weinberg equilibrium
IGF1
Insulin-like growth factor 1
MAF
Minor allele frequency
OR
Odds ratio
PB
Population-based
SNP
Single nucleotide polymorphism
TGCT
Testicular germ cell tumors

Background

The occurrence of cancer depends on both genetic and environmental factors [1, 2]. Relevant environmental factors include pollution, tobacco and alcohol intake, overweight, and infection [3]. Studies based on twins have found that genetic factors are also an important risk factor for cancer [2, 4]. Recently, the role of SNPs in the occurrence and development of cancer has attracted increasing attention [5]. The SNPs that are associated with cancer risk may act as biomarkers for cancer diagnosis [6, 7].
IGF1 is a growth factor that involves in many important biological and pathological processes [8, 9]. The important functions of IGF1 are promoting cell proliferation and inhibiting apoptosis [10]. IGF1 has also been reported to be involved in cancer development [11]. Plasma IGF1 levels depend on many factors, such as BMI, but gene is also an important factor [12, 13]. Many studies have reported that several IGF1 SNPs affect plasma IGF1 levels and thus influence the risk of cancer [14, 15].
rs1520220 is located in intron 3 of IGF1 gene which might lead to alternative splicing and a subsequent change in protein function [16]. It has been reported that rs1520220 G to C substitution leads to increased plasma IGF1 level, increasing cancer risk as a result [13, 17]. However, the studies regarding the relationship between rs1520220 and cancer susceptibility are inconsistent [1825]. For instance, Al-Zahrani et al. reported that rs1520220 increased susceptibility to breast cancer [18], but Li et al. suggested that rs1520220 was not related to susceptibility to breast cancer [25]. Considering the disagreement between these studies, we performed a meta-analysis of the associations between rs1520220 and cancer susceptibility to review these results and draw a more accurate conclusion.

Methods

Search strategy

We searched for relevant studies in three databases: PubMed, Embase, and Web of Science. The search conditions limited the language to English and the data of publication prior to February 28, 2018. The following keywords were used: “IGF1 or IGF-1 or insulin-like growth factor 1 or rs1520220,” “cancer or tumor or carcinoma,” and “SNP or polymorphism or variant or mutation.” We also checked the references of the identified articles to ensure that we obtained all potentially relevant studies.

Inclusion and exclusion criteria

The inclusion criteria of this meta-analysis are as follows: studies must (1) concern the relationship between rs1520220 and cancer susceptibility, (2) be case-control or cohort study, and (3) contain sufficient genotyping data to allow for the pooling of the results (the GG, GC, and CC genotype frequencies in the case and control groups were provided directly or could be calculated from the provided data). The exclusion criteria are as follows: (1) when subjects of two studies overlap, the one containing fewer subjects was excluded, and (2) reviews and meta-analyses are excluded.

Data extraction

The following information was extracted from the included studies by two authors independently: first author’s name, year of publication, country, cancer type, ethnicity, genotyping methods, control source, genotype distributions of cases and controls, and Hardy-Weinberg equilibrium (HWE) for controls. Disagreements were resolved via discussion.

Quality score

We assessed the quality of the included studies based on the following five factors [26]: case source, control source, specimens used for determining genotypes, HWE in controls, and total sample size (Additional file 1: Table S1). A perfect score was 15.

Statistical analysis

We estimated the strengths of the associations using pooled ORs with corresponding 95% CIs. Five genetic models are employed: the allele model (C vs. G), the homozygote model (CC vs. GG), the heterozygote model (GC vs. GG), the dominant model (CC + GC vs. GG), and the recessive model (CC vs. GC + GG). The heterogeneity was evaluated using a Q test and quantified by I2 [27]. When heterogeneity not exists (P > 0.1), the fixed-effects model was used [28]. Otherwise, the random-effects model was applied [29]. Hardy-Weinberg equilibrium (HWE) for controls was assessed using a chi-squared test. P values less than 0.05 were considered to indicate significant disequilibrium. Stratified analyses were conducted by ethnicity, cancer type, and quality score. Only results synthesized from no fewer than two studies are shown. Sensitivity analyses were performed via metainf command which investigates the influence of each individual study on the overall meta-analysis summary estimate by omitting each study in turn [30]. Publication bias was assessed using Begg’s test and Egger’s test [31, 32]. All statistical analyses were performed using the STATA software (Version 12.0; Stata Corporation, College Station, TX, USA).

Results

Characteristics of the studies

We obtained 2086 relevant articles through database searching after removing duplicates. Then, by screening the titles and abstracts, we excluded 1953 articles, and 133 articles remained. We read the full texts of these 133 articles and ultimately identified eight articles that meet the inclusion criteria (Fig. 1), which involved 12,884 cases and 58,304 controls. The characteristics of the included studies are shown in Table 1. Among these eight studies, four were carried out in Asian populations, two were carried out in Caucasian populations, and two were carried out in mix populations. Four of them concerned breast cancer, and four concerned other cancers including testicular germ cell tumors (TGCT), stomach cancer, pancreatic cancer, and colorectal cancer. Seven of the included studies had quality scores of no less than 12. The distributions of the genotypes and allele frequencies in the cases and controls are shown in Table 2.
Table 1
Characteristics of the studies included in the meta-analysis
First author
Year
Country/region
Ethnicity
Cancer type
Genotyping method
Control source
AI-Zahrani [18]
2006
Europe
Caucasian
Breast cancer
TaqMan
PB
Chia [19]
2008
USA
Mix
TGCT
TaqMan
PB
Patel [20]
2008
USA or Europe
Mix
Breast cancer
TaqMan
PB
Ennishi [21]
2011
Japan
Asian
Stomach cancer
TaqMan
HB
Nakao [22]
2011
Japan
Asian
Pancreatic cancer
TaqMan
HB
Qian [23]
2011
China
Asian
Breast cancer
TaqMan
HB
Simons [24]
2015
Netherlands
Caucasian
Colorectal cancer
SEQUENOM® MassARRAY®
PB
Li [25]
2016
China
Asian
Breast cancer
TaqMan
PB
TGCT testicular germ cell tumors, PB population-based, HB hospital-based
Table 2
IGF1 rs1520220 polymorphism genotype distribution and allele frequency in cases and controls
 
Genotype (N)
Allele frequency (N)
HWE
Score
 
Case
Control
Case
Control
 
Total
GG
GC
CC
Total
GG
GC
CC
G
C
G
C
  
AI-Zahrani [18]
2036
1388
569
79
2194
1525
617
52
3345
727
3667
721
0.261
15
Chia [19]
568
378
169
21
698
452
209
37
925
211
1113
283
0.052
15
Patel [20]
6584
329
2207
4048
8424
440
2707
5277
2865
10,303
3587
13,261
< 0.001
12
Ennishi [21]
703
148
357
198
1462
361
728
373
653
753
1450
1474
0.877
12
Nakao [22]
176
33
97
46
1402
347
697
358
163
189
1391
1413
0.833
12
Qian [23]
403
71
189
143
403
78
193
132
331
475
349
457
0.620
11
Simons [24]
2274
85
691
1498
43,561
1384
12,689
29,488
861
3687
15,457
71,665
0.673
15
Li [25]
140
38
58
44
160
36
69
55
134
146
141
179
0.113
12
HWE Hardy-Weinberg equilibrium

Meta-analysis

We investigate the role of rs1520220 polymorphisms in cancer susceptibility via pooled OR and 95%Cl. Only results synthesized from no fewer than two studies are shown. In the overall analysis, we did not find positive associations between rs1520220 and cancer susceptibility (Table 3).
Table 3
Meta-analysis of the association between IGF1 rs1520220 polymorphism and cancer susceptibility
Subgroup
No.
C vs. G
CC vs. GG
GC vs. GG
CC + GC vs. GG
CC vs. GC + GG
 
OR (95%Cl)
P OR
P h
OR (95%Cl)
P OR
P h
OR (95%Cl)
P OR
P h
OR (95%Cl)
P OR
P h
OR (95%Cl)
P OR
P h
Overall
8
1.01 (0.95–1.08)*
0.715
0.026
1.08 (0.90–1.30)*
0.415
0.010
1.05 (0.97–1.13)
0.268
0.374
1.05 (0.97–1.13)
0.237
0.163
1.02 (0.91–1.13)*
0.773
0.026
Caucasian
2
1.00 (0.84–1.20)*
0.953
0.010
1.16 (0.58–2.31)*
0.675
0.001
0.98 (0.87–1.10)
0.743
0.330
0.97 (0.77–1.21)*
0.762
0.08
1.21 (0.68–2.15)*
0.524
0.002
Asian
4
1.10 (1.00–1.21)
0.040
0.455
1.22 (1.01–1.47)
0.040
0.426
1.17 (0.99–1.39)
0.066
0.382
1.19 (1.01–1.39)
0.033
0.324
1.10 (0.95–1.26)
0.215
0.762
Breast cancer
4
1.00 (0.95–1.05)
0.978
0.130
1.15 (0.87–1.51)*
0.320
0.053
1.04 (0.94–1.15)
0.425
0.713
1.05 (0.96–1.15)
0.289
0.703
1.11 (0.86–1.42)*
0.428
0.016
Quality score ≥ 12
7
1.01 (0.94–1.08)*
0.875
0.021
1.07 (0.87–1.31)*
0.542
0.006
1.04 (0.96–1.13)
0.292
0.275
1.04 (0.97–1.12)
0.283
0.112
1.01 (0.90–1.13)*
0.922
0.023
OR odds ratio, 95% CI 95% confidence interval, POR, pool p value; Ph, p value of heterogeneity test
*Indicates that the OR, 95% Cl, and corresponding POR were calculated based on the random-effects model; otherwise, the fixed-effects model was used. Italic values are statistically significant (P < 0.05)
In the analysis stratified by ethnicity, we found that rs1520220 was significantly associated with increased cancer susceptibility in Asian populations (Table 3 and Fig. 2, allele model OR = 1.10, 95%Cl = 1.00–1.21, p = 0.040; homozygote model OR = 1.22, 95%Cl = 1.01–1.47, p = 0.040; dominant model OR = 1.19, 95%Cl = 1.01–1.39, p = 0.033). Thus, no significant association was detected in Caucasian populations (Table 3 and Fig. 2).
In the analysis stratified by cancer type, the results show that rs1520220 was not associated with susceptibility to breast cancer (Table 3). Also, the results synthesized from studies that scored no less than 12 did not exhibited any differences from the results of the overall analysis (Table 3).

Sensitivity analysis

We performed sensitive analysis and found there was not an individual study that affected the results of the overall analysis (Fig. 3 and Additional file 1: Table S2), indicating that in this meta-analysis, our results are relatively stable.

Publication bias

Begg’s test and Egger’s test were performed to assess the publication bias among the included studies. No publication bias was detected in the present meta-analysis (Fig. 4 and Table 4).
Table 4
Publication bias analysis
Genetic model
Egger’s test
Begg’s test
t
95%Cl
p
p
C vs. G
0.85
− 1.731~3.568
0.429
0.902
CC vs. GG
0.23
− 3.080~3.724
0.824
0.902
GC vs. GG
0.14
− 2.255~2.537
0.890
1.000
CC + GC vs. GG
− 0.09
− 2.981–2.760
0.928
0.902
CC vs. GC + GG
1.11
− 1.099–2.912
0.311
0.902

Discussion

Many SNPs have been reported to be associated with cancer susceptibility and thus may have the potentiality as biomarkers for clinical diagnosis [57]. Thus far, with the improvement of living standards in more and more developing countries, obesity and lifestyle-related cancers have been on the increase [33, 34]. IGF1 has been reported to relate to be associated with the cancer susceptibility, especially cancers caused by obesity, due to its important role in cell proliferation [35].
Several IGF1 SNPs have been reported to be associated with cancer susceptibility [3639]. These SNPs include rs1520220, rs6214, rs6220, rs35767, and rs5742612. Of these, rs6214 and rs6220 are located in the 3′-UTR region of the IGF1 gene. It has been reported that rs6214 is associated with increased esophageal adenocarcinoma (EAC) and head and neck cancer (HNC) susceptibility in women [39] and that rs6220 is associated with increased prostate cancer susceptibility [40]. The rs35767 and rs5742612 SNPs are located in the promoter region of the IGF1 gene. It has been reported that rs35767 is significantly associated with increased susceptibility of childhood acute lymphoblastic leukemia (ALL) [41] and that rs5742612 is associated with increased susceptibility to prostate cancer [42].
rs1520220 is an SNP that is located in the intron of the IGF1 gene, and it has a minor allele frequency (MAF) about 10~ 40% in the populations included in the human 1000 Genomic Project phase 3 (Additional file 1: Table S3). We paid special attention to rs1520220 because it has been reported to be associated with plasma IGF1 levels in many studies and thus associated with cancer susceptibility [13, 17, 18].
In this meta-analysis, we systematically searched for literature on IGF1 SNPs and cancer in three important databases (PubMed, Embase, and Web of Science). After removing duplicate documents, 2086 related articles were initially obtained, which ensured the maximum possible recall rate. Through meta-analysis, we found that rs1520220 was not related to cancer susceptibility in the overall analysis based on the present epidemiology studies. Thus, in the analysis stratified by ethnicity, we revealed that rs1520220 increased cancer susceptibility in Asian populations.
The present studies regarding the effect of IGF1 rs1520220 polymorphism on serum IGF1 are inconsistent [13, 18]. In brief, rs1520220 may influence circulating IGF1 expression by altering the secondary structure of the RNA or DNA [16], and this effect may be enhanced by dietary factors [43]. Therefore, we infer that rs1520220 affects cancer susceptibility in Asians but not other populations due to the combined effects of genetic and environmental factors. The mechanism via which rs1520220 affects serum levels must be investigated in the future.
Our meta-analysis has several limitations. Firstly, we found that rs1520220 increased cancer susceptibility in Asians. The molecular mechanism via which the rs1520220 C allele increases plasma IGF1 levels and thus cancer risk remains unclear. Secondly, we did not consider potential external factors, such as gender, age, diet, and tobacco and alcohol intake habits or gene-gene interactions. Thirdly, the number of studies included in the meta-analysis is limited. We only included studies written in English, and important-related studies in other languages may have been overlooked.

Conclusion

The present meta-analysis showed that IGF1 rs1520220 is not significantly associated with overall cancer susceptibility. However, we did find that rs1520220 significantly increased cancer susceptibility in Asian populations. We also suggest that rs1520220 was not associated with susceptibility to breast cancer. There is a need for additional well-designed epidemiology and molecular biology studies to verify these conclusions and provide new insights into the role of SNPs in the etiology of cancer.

Funding

This work was supported by grants from the National Natural Science Foundation of China (grant no. 81601826).

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.
Not applicable
Not applicable

Competing interests

The authors declare that they have no competing interests.

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Literatur
4.
Zurück zum Zitat Sturm RA. Skin colour and skin cancer––MC1R, the genetic link. Melanoma Res. 2002;12:405–16.CrossRefPubMed Sturm RA. Skin colour and skin cancer––MC1R, the genetic link. Melanoma Res. 2002;12:405–16.CrossRefPubMed
17.
Zurück zum Zitat Gu F, Schumacher FR, Canzian F, Allen NE, Albanes D, Berg CD, Berndt SI, Boeing H, Bueno-de-Mesquita HB, Buring JE, et al. Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer. Cancer Epidemiol Biomark Prev. 2010;19:2877–87. https://doi.org/10.1158/1055-9965.EPI-10-0507.CrossRef Gu F, Schumacher FR, Canzian F, Allen NE, Albanes D, Berg CD, Berndt SI, Boeing H, Bueno-de-Mesquita HB, Buring JE, et al. Eighteen insulin-like growth factor pathway genes, circulating levels of IGF-I and its binding protein, and risk of prostate and breast cancer. Cancer Epidemiol Biomark Prev. 2010;19:2877–87. https://​doi.​org/​10.​1158/​1055-9965.​EPI-10-0507.CrossRef
18.
Zurück zum Zitat Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P, et al. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet. 2006;15:1–10. https://doi.org/10.1093/hmg/ddi398.CrossRefPubMed Al-Zahrani A, Sandhu MS, Luben RN, Thompson D, Baynes C, Pooley KA, Luccarini C, Munday H, Perkins B, Smith P, et al. IGF1 and IGFBP3 tagging polymorphisms are associated with circulating levels of IGF1, IGFBP3 and risk of breast cancer. Hum Mol Genet. 2006;15:1–10. https://​doi.​org/​10.​1093/​hmg/​ddi398.CrossRefPubMed
22.
Zurück zum Zitat Nakao M, Hosono S, Ito H, Watanabe M, Mizuno N, Yatabe Y, Yamao K, Ueda R, Tajima K, Tanaka H, et al. Interaction between IGF-1 polymorphisms and overweight for the risk of pancreatic cancer in Japanese. Int J Mol Epidemiol Genet. 2011;2:354–66.PubMedPubMedCentral Nakao M, Hosono S, Ito H, Watanabe M, Mizuno N, Yatabe Y, Yamao K, Ueda R, Tajima K, Tanaka H, et al. Interaction between IGF-1 polymorphisms and overweight for the risk of pancreatic cancer in Japanese. Int J Mol Epidemiol Genet. 2011;2:354–66.PubMedPubMedCentral
28.
Zurück zum Zitat Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMed Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst. 1959;22:719–48.PubMed
29.
Zurück zum Zitat DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRefPubMed DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.CrossRefPubMed
31.
Zurück zum Zitat Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.CrossRefPubMed Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.CrossRefPubMed
40.
Zurück zum Zitat Johansson M, McKay JD, Wiklund F, Rinaldi S, Verheus M, van Gils CH, Hallmans G, Balter K, Adami HO, Gronberg H, et al. Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels. J Clin Endocrinol Metab. 2007;92:4820–6. https://doi.org/10.1210/jc.2007-0887.CrossRefPubMed Johansson M, McKay JD, Wiklund F, Rinaldi S, Verheus M, van Gils CH, Hallmans G, Balter K, Adami HO, Gronberg H, et al. Implications for prostate cancer of insulin-like growth factor-I (IGF-I) genetic variation and circulating IGF-I levels. J Clin Endocrinol Metab. 2007;92:4820–6. https://​doi.​org/​10.​1210/​jc.​2007-0887.CrossRefPubMed
Metadaten
Titel
The association between IGF1 gene rs1520220 polymorphism and cancer susceptibility: a meta-analysis based on 12,884 cases and 58,304 controls
verfasst von
Gui-Ping Xu
Wei-Xian Chen
Wen-Yue Xie
Li-Fang Wu
Publikationsdatum
01.12.2018
Verlag
BioMed Central
Erschienen in
Environmental Health and Preventive Medicine / Ausgabe 1/2018
Print ISSN: 1342-078X
Elektronische ISSN: 1347-4715
DOI
https://doi.org/10.1186/s12199-018-0727-y

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