The relationship between polymorphism of IGF2BP2 gene rs4402960 and risk of pan-cancer: a meta-analysis and a bioinformatics analysis

doi:10.21203/rs.3.rs-3130789/v1

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The relationship between polymorphism of IGF2BP2 gene rs4402960 and risk of pan-cancer: a meta-analysis and a bioinformatics analysis

https://doi.org/10.21203/rs.3.rs-3130789/v1

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Background

Although some studies have established the relationship between insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) rs4402960 polymorphism and the pathogenesis of cancer. But the results are contradictory. We conducted a meta-analysis to assess the relationship between IGF2BP2 gene polymorphism and cancer risk. Furthermore, the expression of IGF2BP2 in pan-cancer tissues and normal tissues was further analyzed from the perspective of bioinformatics analysis.

Methods

Using published case–control studies up to August 15, 2021, the literature search included searches of PubMed, Web of Science, and EMBASE to determine the samples that met the inclusion criteria. The heterogeneity test was used in five genetic models. Odds ratios (OR), 95% confidence intervals (CI), and p-values were used to evaluate the combined effects of various genetic models. Sensitivity analysis and publication bias were also performed. Transcriptomic information on IGF2BP2 and corresponding clinical information was downloaded from the TCGA and GTEx databases. Differences in IGF2BP2 expression between various kinds of cancer tissues and normal tissues were analysed.

Results

This meta-analysis contained 6 case–control studies, with 5,908 cases and 7,890 controls. There was only an association between IGF2BP2 rs4402960 polymorphism and cancer risk in the heterozygous genetic model (heterozygous: OR = 1.080, 95% CI = 1.003–1.163, p = 0.041). The sensitivity analysis examined the effect of various research studies on the combined OR by deleting one study by turns. No publication bias was found in the genetic models. We found that IGF2BP2 was over-expressed in breast cancer, non-small cell lung cancer, colorectal cancer and esophageal cancer (P < 0.001).

Conclusions

The results of meta-analysis showed that IGF2BP2 gene polymorphism may be related to cancer risk. IGF2BP2 was over-expressed in Breastcancer, Non-small Cell Lung Cancer, Colorectal Cancer, Breast cancer and esophageal cancer tissues. IGF2BP2 may be used as an index of early cancer screening and prognosis treatment.

IGF2BP2

genetic polymorphism

cancer risk

meta-analysis

bioinformatic analysis

Cancer poses a serious threat to human health and life, and its incidence and mortality are rapidly growing worldwide¹. Diet, tobacco smoking, living habits, cytometaplasia, and genetic factors are among the contributing factors to tumor development^2,3. Gene polymorphism has an important impact on cancer development. Research on the mechanism of tumor genes has begun receiving increasing attention. Several studies have indicated that the insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) gene may be associated with cancer risk, such as oral cancer⁴. non-small-cell lung cancer (NSCLC)⁵, and esophagogastric junction adenocarcinoma (EGJA)⁶. Liu’s results indicate that IGF2BP2 polymorphism may be an independent predictor of chemotherapy response⁷.

The IGF2BP2 base contains 16 exons and is located at the 3q27.2 locus of chromosome 3⁸. IGF2BP2 belongs to an RNA-binding protein that is a post-qualitative regulator of messenger RNA (mRNA) localization, stability, and conversion control⁹. Current research shows that the IGF2BP2 gene is related to the occurrence and development of diabetes^10–12. IGF2BP2 is a key gene in the m6A signaling pathway and has recently been shown to play a role in the occurrence and development of various cancers^13–17. Wassim et al show that rs440960 was positively associated with BC¹⁸. IGFBP2 is overexpressed in many malignant tumors and is related to a tumor’s malignancy, which suggests that it may be involved in the occurrence of tumors.

To date, there have been seven reports about the relationship between IGF2BP2 gene rs4402960 polymorphism and cancer. However, the results of these studies are discrepant. However, the results of these studies are discrepant. For example, the results of Chou et al.⁴ and Liu et al.¹⁹ showed that the rs4402960 gene polymorphism can increase cancer risk. The results of Chen et al.⁵ suggest that the rs4402960 gene polymorphism may reduce the susceptibility to NSCLC. Therefore, to explore whether there is a relationship between IGFBP2 rs4402960 polymorphism and the pathogenesis of cancer. We conducted this meta-analysis of related study. In addition, the expression of IGFBP2 in pan-cancer was analyzed by bioinformatics. To explore the value of IGFBP2 in the diagnosis and treatment of cancer.

2.1. Literature search and inclusion criteria

As of June 15, 2023, we conducted literature searches in three databases: PubMed, EMBASE, and Web of Science. We searched in English using the following terms: “Insulin-like growth factor 2 mRNA-binding protein 2” or “IGF2BP2,” “polymorphism” or “mutation” or “variant” or “SNP,” and “tumor” or “neoplasm” or “malignant tumor” or “malignant neoplasm” or “carcinoma” or “human carcinoma” or “cancer” and "rs4402960". All articles included in this meta-analysis conformed to the inclusion criteria: (1) cohort or case–control study; (2) the data type can extract research on calculated OR, 95% CI, and Hardy–Weinberg equilibrium (HWE); and (3) the DNA genotype analysis method is clear, and the source of cases and controls is reliable. Studies were eliminated if one of the following terms existed: (1) case reports, review articles, letters, editorials, and conference summaries; (2) pedigree study.

2.2. Data Extraction and Quality Assessment

We extracted data from the qualified studies. The data contained the first author, publication time, country, race, sample, genotype frequency of cases and controls, type of cancer, genotyping method, and specimen source. We used the modified Newcastle–Ottawa Scale to estimate the quality of the research. The HWE was used to calculate the research data in the control population to analyze the representativeness of the research.

2.3. Statistical Analysis

Five genetic models of homozygous (TT V GG), heterozygous (GT V GG), allele (T V G), dominant (TT + GT V GG), and recessive (TT V GG + GT) were analyzed to calculate the combined OR value and 95% CIs. Heterogeneity evaluation was done via the chi-square q test and I2 statistic. The random-effects model(REM) was adopted. Publication bias was evaluated by Begg’s funnel plot and Egger’s test. All tests are two-tailed and consider p ≤ 0.05 statistically significant. Stata version 12.0 software (Stata Corporation, College Station, TX, USA) was used for statistical analysis. All analyses were based on previous published studies, thus no ethical approval and patient consent are required.

2.4. Differential expression of IGF2BP2 in pan-cancer and several cancers

Firstly, the differential expression level of IGF2BP2 in pan-cancer was analyzed. To determine the differences in IGF2BP2 expression in breast cancer, non-small cell lung cancer, colorectal cancer and esophageal cancer tissues and normal tissues. The RNAseq data (level3) and corresponding clinical information for breast cancer were obtained from the Cancer Genome Atlas (TCGA) dataset (https://portal.gdc.com). GTEx data from V8 (https://gtexportal.org/home/datasets). All the data used were standardized TPM data, and the data distribution was close to the normal distribution. Thus, sample significance for both groups was assessed by wilcox's test for difference between the two groups. This is achieved through the R software package ggplot2. Statistical analysis was performed using R software v4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). P-values < 0.05 were considered statistically significant.

3. 1. Literature selection and study characteristics

This study included seven articles, which provided 5,908 cases and 7,890 controls that were suitable for meta-analysis. The flowchart of the literature retrieval process is shown in Fig. 1. The quality of the research is evaluated with a score of 6–8. There are 4 articles whose HWE test p-value is less than 0.05. The baseline information of the articles are shown in Table 1.

Table 1

Characteristics and quality assessment of the included studies.
Author (Refs.)	Year	Country	Ethnicity	Cancer type	Source of controls	Genotyping methods	Cases GG/GT/TT	Controls GG/GT/TT	P∗	Quality score†
Chou	2020	China	Chinese	Oral	HB	TaqMan	799/483/67	710/413/75	0.155	7
Liu	2015	China	Chinese	Breast	HB	PCR-LDR	285/244/35	236/144/14	0.159	7
Chen	2018	China	Chinese	NSCLC	HB	SNPscan	306/185/30	603/344/82	0.001	6
Qiu	2017	China	Chinese	ESCC	HB	SNPscan	294/179/30	872/506/111	0.002	8
Sainz	2012	America	Caucasian	Colorectal	HB	KASPar	892/745/147	884/716/166	0.230	7
Tang	2019	China	Chinese	EGJA	HB	SNPscan	408/258/33	924/508/106	0.002	7
Wassim	2023	Tunis	Caucasian	Breast	HB	TaqMan	283/141/64	294/142/40	< 0.001	6
NSCLC = non-small-cell lung cancer, ESCC = esophageal squamous cell carcinoma, EGJA = esophago gastric junction adenocarcinoma,
HB = hospital-based, PCR-LDR = PCR-ligase detection reaction
∗ HWE in the control group.
† assessed by the NOS for case-control studies.

3.2. Meta-analysis results

The random-effects model was used to analyze the study. The heterogeneity test results of the meta-analysis, which were based on the p-value, I2 and combined effect value Z test of the IGF2BP2 rs4402960 polymorphism, are listed in Table 2. However, there is relevance between IGF2BP2 rs4402960 polymorphism and cancer risk in the heterozygous genetic model (heterozygous: OR = 1.080, 95% CI = 1.003–1.163, p = 0.041). (Table 2 and Fig. 2).

Table 2
Genetic model	Pooled OR (95% CI)	Heterogeneity test I2 (%) P for Q test		Analysis model	Z test	P
Homozygous
Overall	0.952 (0.738–1.228)	65.7	0.008	REM	0.38	0.705
Heterozygous
Overall	1.080 (1.003–1.163)	0.0	0.557	REM	2.04	0.041
Allelic
Overall	1.033 (0.943–1.133)	58.6	0.025	REM	0.70	0.482
Dominant
Overall	1.061 (0.975–1.154)	26.7	0.225	REM	1.37	0.170
Recessive
Overall	0.921 (0.720–1.178)	64.8	0.009	REM	0.66	0.512
Meta-analysis results of overall and subgroup analysis.
CI = confidence interval, OR = odds ratio, REM = random-effects model.

3.3. Sensitivity analysis and Publication bias

The sensitivity analysis examined the effect of various research studies on the combined OR by deleting one study by turns. The results show that the combined OR is stable after removing any study in any model (Fig. 3). The publication bias of the selected articles was detected through Begg’s test. No publication bias was found in the genetic models (Fig. 4).

3.4. The Different Expressions of IGF2BP2 in pan-cancer, breast cancer, non-small cell lung cancer, colorectal cancer and esophageal cancer and normal Tissues

The results of evaluating the difference of IGF2BP2 expression between pan-cancer (ACC/BRCA/CESC/CHOL/COAD/DLBC/ESCA/GBM/HNSC/KIRC/KIRP/LGG/LIHC/LUAD/LUSC/OV/PAAD/PCPG/PRAD/READ/SKCM/STAD/TGCT/THCA/UCS) and normal tissues are shown in Fig. 5a, Fig. 5b, Fig. 5c and Fig. 5d. To evaluate the IGF2BP2 expression in breast cancer, non-small cell lung cancer, colorectal cancer, breast cancer and esophageal cancer and normal tissues. The IGF2BP2 expression data were collected from 1101 breast cancer tissues and 572 normal tissues (Fig. 6a), the IGF2BP2 expression data were collected from 1017 NSCLC tissues and 627 normal tissues (Fig. 6b), the IGF2BP2 expression data were collected from 620 colorectal cancer tissues and 789 normal tissues (Fig. 6c), the IGF2BP2 expression data were collected from 163 esophageal cancer tissues and 1456 normal tissues (Fig. 6d). IGF2BP2 was overexpressed in breast cancer, non-small cell lung cancer, colorectal cancer, breast cancer and esophageal cancer tissues compared to normal tissues (P < 0.001).

This meta-analysis included seven published research articles on the relevance between the rs4402960 G > T variant and carcinoma risk. There is relevance between IGF2BP2 rs4402960 polymorphism and cancer risk in the heterozygous genetic model (GT V GG). This result provide further evidence for the IGF2BP2 gene on cancer risk. The available evidence suggests that IGF2BP2 plays an important role in cancer progression. This discovery aligns with the conclusions obtained by other research results. For example, it is reported that IGF2BP2 is widely involved in embryonic development, neuronal differentiation and metabolic physiological processes²⁰. The imbalance of its expression is related to carcinogenesis^21–23. IGF2BP2 participates in the development of cancer by communicating with different RNAs such as microRNA (miRNA), messenger RNA and long non-coding RNA (lncRNA)²⁴. According to previous research reports, Liu et al. found that Dominant model (GT + TT) and allelic model of rs4402960 polymorphism may significantly increase the risk of breast cancer¹⁹. As with the study of Liu et al., Chou et al came to a similar conclusion after their study. Patients with rs4402960 GT + TT genotype have an increased risk of advanced clinical stage, tumor enlargement, and progression of lymph node metastasis. These reveal that rs4402960 gene polymorphism may be related to the pathogenesis of cancer. Cancer is a complex disease. Multiple determinants such as different genetic backgrounds and linkage disequilibrium patterns of different races are all possible reasons for this difference. It should be noted that the three articles in the control group (Chen et al, .2018; Qiu et al, .2017; Tang et al, .2019; Wassim et al, .2023) are inconsistent with HWE. After omitting these 4 articles, recalculate the combined OR. The results showed that there was no statistical change in the corresponding combined ORs. Therefore, our results are statistically robust. The Begg’s funnel chart and Egger test confirmed this result.

The expression of IGF2BP2 in breast cancer, non-small cell lung cancer, colorectal cancer and esophageal cancer tissues and normal tissues was compared by database. IGF2BP2 was overexpressed in breast cancer, non-small cell lung cancer, colorectal cancer, breast cancer and esophageal cancer tissues. According to the research, IGF2BPs is related to pan-cancer, its prognosis and tumor immune microenvironment²⁵. The IGF2BP2 is the direct target of miR-141, and the expression of IGF2BP2 promotes the growth of pancreatic cancer cells by activating PI3K/Akt signaling pathway in vitro and in vivo¹⁵. IGF2BP2 promotes the growth of hepatocellular carcinoma through m6A-FEN1 dependent mechanism¹³. Besides, IGF2BP2 is involved in the occurrence and development of many cancers^26–30. IGF2BP2 has diagnostic value in the diagnosis and treatment of pan-cancer.

The findings of this study should be interpreted with caution, considering its limitations. First, the small sample size of our research and the number of articles are the main shortcomings. Because there are few articles included in the meta-analysis. Inadequate Begg's funnel chart and Egger's test make it inconvenient to determine the source of heterogeneity. Accordingly, more experimental results are needed to prove this conclusion in the future. Secondly, the mRNA and protein levels of IGF2BP2 were evaluated in our study, and their levels need to be further verified by human tissues in future studies. Additional verification of the prognosis and diagnostic values of public data sets is needed to support our current results. More efforts are needed to explore the role of IGF2BP2 in cancer and the value of IGF2BP2 as a potential target of anticancer therapy.

In general. The results of meta-analysis showed that IGF2BP2 gene polymorphism may be related to cancer risk. IGF2BP2 was over-expressed in Breastcancer, Non-small Cell Lung Cancer, Colorectal Cancer, Breastcancer and esophageal cancer tissues. IGF2BP2 may be used as an index of early cancer screening and prognosis treatment. Moreover, through the comprehensive analysis of the diagnostic value of IGF2BP2 in pan-cancer. IGF2BP2 may be a potential target for cancer treatment, effective prognosis and diagnosis.

Authors’ Contributions

Fengke Lu designed the meta-analysis and bioinformatic analysis; Fengke Lu and Hongyu Zhang collected and analyzed the data; Wei Zhang performed the quality assessment; Fengke Lu wrote the article; and all the authors approved submission.

Conflicts of Interest

The authors claim no competing economic interests.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Acknowledgments

The results here are based on data generated by the TCGA research network.

Data Availability Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

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You are reading this latest preprint version

The relationship between polymorphism of IGF2BP2 gene rs4402960 and risk of pan-cancer: a meta-analysis and a bioinformatics analysis

Status:

Version 1

Abstract

Background

Methods

Results

Conclusions

Figures

1. Introduction

2. Material and Methods

2.1. Literature search and inclusion criteria

2.2. Data Extraction and Quality Assessment

2.3. Statistical Analysis

2.4. Differential expression of IGF2BP2 in pan-cancer and several cancers

3. Results

3. 1. Literature selection and study characteristics

3.2. Meta-analysis results

3.3. Sensitivity analysis and Publication bias

4. Discussion

Declarations

References

Status:

Version 1