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The carcinogenic effect of the MMP9 rs3918242 polymorphism on the risk of cancer of the digestive system: evidence from a meta-analysis

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The carcinogenic effect of the MMP9 rs3918242 polymorphism on the risk of cancer of the digestive system: evidence from a meta-analysis

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THE CARCINOGENIC EFFECT OF THE MMP9 RS3918242
POLYMORPHISM ON THE RISK OF CANCER OF THE
DIGESTIVE SYSTEM: EVIDENCE FROM A META-
ANALYSIS

by

Yina Liu

A Thesis Presented to the
FACULTY OF THE USC KECK SCHOOL OF MEDICINE
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
BIOSTATISTICS

May 2021

Copyright 2021 Yina Liu
ii
Table of Contents
List of Tables ..................................................................................................................................................... iii
List of Figures .................................................................................................................................................... iv
Abstract .............................................................................................................................................................. v
1. Introduction .................................................................................................................................................... 1
2. Materials and methods ................................................................................................................................... 3
2.1 Literature Review on Meta-analysis .................................................................................................................. 3
2.2 Literature research ............................................................................................................................................ 4
2.3 Study Selection and Data Extraction ................................................................................................................. 4
2.4 Statistical Analysis ............................................................................................................................................. 5
3. Results ............................................................................................................................................................. 6
3.1 Characteristics of the studies ............................................................................................................................. 6
3.2 Quantitative synthesis and subgroup analysis ................................................................................................... 8
3.3 Publication bias and Sensitivity analysis ........................................................................................................... 9
3.4 Heterogeneity analysis ..................................................................................................................................... 11
4. Discussion ..................................................................................................................................................... 13
REFERENCES ................................................................................................................................................. 16

iii
List of Tables
Table 1 | Association between the MMP9 rs3918242 polymorphism and cancer risk ................ 21

iv
List of Figures
Fig.1 | Workflow expresses information through the steps of systematic review to the meta-analysis
in this research. ............................................................................................................................... 7
Fig.2 | Forest plot of the association between the MMP9 rs3918242 polymorphism and cancer risk
in the homozygote model. ............................................................................................................... 9
Fig.3 | Funnel plot of the 29 studies included in the homozygote model of this meta-analysis. .. 10
Fig.4 | Sensitivity analysis for the homozygote model. ................................................................ 11
Fig.5 | Galbraith plot for the heterozygote model ......................................................................... 12
Fig.6 | Galbraith plot for the dominant model. ............................................................................ 13

v
Abstract
Meta-analysis is a suitable approach to produce a pooled estimate closest to the unknown
common truth by combining the results of multiple scientific studies that address the same
question. This meta-analysis was performed to quantitively verify the genetic effect of the
MMP9 rs3918242 polymorphism on cancer risk of the digestive system. In total, twenty-nine
studies with 4,671 cases and 5,876 controls were included by a systematic literature search
within four electronic databases. R scripts were developed to measure odds ratios (ORs) and
corresponding 95% confidence interval (95%CIs) to assess the impact of the polymorphism.
Pooled estimates statistically revealed the significant carcinogenic effect of the MMP9
rs3918242 polymorphism homozygote genotypes on the digestive system, especially for liver
and stomach. Given the statistical significance, the results suggested the MMP9 rs3918242
polymorphism homozygosity may associate with increasing risk of liver and gastric cancer.

Keywords: MMP9, polymorphism, meta-analysis, cancer, digestive system
1
1. Introduction
Cancer of the digestive system, which is ever touted as a severe health enemy around the world,
is featured by notorious fame for its high morbidity as well as mortality. As human beings has
better understanding of human genome structure and gene functions in an ever-growing speed,
people has reached a consensus in cancer, whose susceptibility is reasonably affected by genetic
variations made up of single nucleotide polymorphisms (SNP) (Deng et al., 2017).
Regarding the wide functions of pathological procedures in relevance to cancer, the Gelatinase
B/Matrix metallopeptidase 9 (MMP9) gene, which has membership of the Matrix
metalloproteinases (MMPs) family, harbors implication of a biomarker as well as potential
therapeutic target (Roy et al., 2009). It is postulated that high expression of MMP9 is ever exerting
an indispensable part in tumor incidence occurring to a number of various cancer types of the
digestive system, which include gastric cancer (Peng et al., 2017), colorectal cancer (Wu et al.,
2019) in addition to esophageal cancer (Zhang et al., 2015). The MMP9 rs3918242 polymorphism,
functioning as a C to T substitution at position -1562 in its promoter region, is able to exert a
dramatic promotion in on the transcriptional activity of the MMP9 gene (Wu et al., 2013; Hsiao et
al., 2016) as a result of a likely loss of binding affinity to a transcription repressor (Zhang et al.,
1999). According to a former investigation, the polymorphism tends to be trigger a higher risk of
cancer variety (Wu et al., 2019). In consideration of the significance of the MMP9 gene and the
functional polymorphism, it is reasonably suspected to exert a carcinogenic effect upon the human
digestive system.

2
Most recently, several conducted association researches have estimated the impacts exerted by
the MMP9 rs3918242 polymorphism cancer risk. Nevertheless, the scattered evidence is still of
contradiction and inclusion. Meta-analysis is able to throw light upon specified genotypes in
crucial genes which bring about cancer development by providing more reason-based evaluation
of cancer risks, which is a systematic integration of the data out of the isolated independent
epidemiologic researches in virtue of decreasing the impacts of the random errors.
According to a previous meta-analysis, the T allele of the MMP9 rs3918242 polymorphism harbors
relevance to protecting against cancer based on borderline significance (Li et al., 2013). There
were merely ten case-control researches belonging to the inclusion of the meta-analysis; besides,
the limited sample size imposes not only the statistical power but also the validity of the research
results. With a larger number of epidemiological data accumulated, one latest meta-analysis (Hu
et al., 2018) has been committed to deal with the uncertainty in terms of the effects of the MMP9
rs3918242 polymorphism on cancer risks featured by the digestive system. Nevertheless, owing
to the limited strategies on literature searching as well as data extraction, that meta-analysis has
failed to reach a number of associated corresponding case-control researches (Tu et al., 2007;
Zhang et al., 2008; Fu et al., 2009; Wu et al., 2012; Chen et al., 2013; Verma et al., 2015; Zhang
et al., 2015; Radunovic et al., 2016; Liu et al., 2017). That, in consequence, could not supplement
essentially to the accuracy and the carcinogenic impacts of the polymorphism could be realized in
virtue of it. Accordingly, the present research was implemented in virtue of a summarization of
the total current evidence. That was undertaken by summarizing all existing evidence. The
implication is aimed at assessing the extension. The rs3918242 polymorphism works as a risky
factor for digestive system malignancies to its extent.

3
2. Materials and methods
The suggestions from the Preferred Reporting Items for Systematic Review and Meta-Analysis
(PRISMA) group were under strict observation strictly observed throughout the research (Moher
et al., 2009). The exploration comprises a 4-phase flow figure and a 27-item checklist aiming to
complete a meta-analysis or a system review.

2.1 Literature Review on Meta-analysis
Meta-analysis refers to a statistical analysis, oriented with the systematic assessment of the results
of concept-based similar scientific research for deriving conclusions on their focused question.
The total number of scientific researches has been focusing upon the same issue, with the
individual researches which have various error degrees. Thereby, an analysis on the whole
researches with an allocation of varying weighing is bound to offer all-sided results. In brief, the
process of meta-analysis stands for the application of statistical principles oriented with
quantitative researches for the purpose of arriving at a common mean. The major benefits of meta-
analysis come from the aggregation of information contributing to a higher statistical power as
well as a more powerful point estimate, which can be realized out of the measures out of any
individual investigation. The target of this research is to expound the carcinogenic impacts of the
polymorphism in a quantitative way in virtue of summarizing the evidence that has been published.

4
2.2 Literature research
A systematic literature search for the available data sets was conducted in the China National
Knowledge Infrastructure (CNKI) database (http://www.cnki.net/), PubMed
(http://www.ncbi.nlm.nih.gov/pubmed), Web of Science (http://isiknowledge.com/), in addition to
Cochrane library (http://onlinelibrary.wiley.com/cochranelibrary/search/) databases. The
keywords employed in the Boolean expression is composed of definitions for cancer (“Carcinoma”,
“Adenocarcinoma”, “Osteoma”, “Tumor” and “Cancer”), the terms for polymorphism
(“Polymorphism”, “SNP” and “Variant”) along with identifiers oriented with gene symbol
(“MMP9”, “MMP-9” and “Matrix metallopeptidase 9”). The database query conducted by the
search strategy took weekly application, on the basis of the final update on December 15, 2020.

2.3 Study Selection and Data Extraction
The following are the listed inclusion criteria : (1) Full-text accessible; (2) Case-control research
oriented with the connection between cancer risk and the MMP9 rs3918242 polymorphism; (3)
Adequate genotype data for calculating the odds ratio (OR) ; 95% confidence interval (95% CI);
(4) Cancer of the digestive system. In particular, case-control research would not be included in
accordance with the criteria as follows: (1) Data duplicate; (2) No specific cases number and
controls number data; (3) Unhealthy controls with chronic disease. I made all the assessments to
the whole references achieved out of the preliminary literature search abiding by the criteria listed
above.
In consideration of every screened research, the following information shows the recorded contents:
the first author, the year of publication, the region of recruitment, ethnicity, cancer site, sample
5
size, as well as genotype frequencies. Quality evaluation for the included case-control researches
was committed in according to the Newcastle-Ottawa Quality Assessment Scale (NOS, available
at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp ). The scores of 7-9, 4-6, and
0-3 were designated to be high, moderate, and low quality individually.

2.4 Statistical Analysis
The calculation on the pooled odds ratio (OR) and 95% confidence interval (95% CI) was made
for the homozygote model (Minor allele homozygotes versus major allele homozygotes),
heterozygote model (heterozygote carriers versus major allele homozygotes), dominant model (the
integrated minor allele carriers versus major allele homozygotes), and recessive model (minor
allele homozygotes versus the integrated major allele carriers). Cochran’s Chi-square-based Q-test
was employed for testing the heterogeneity assumption. The random effects model on the basis of
the DerSimonian-Laird algorithm (DerSimonian and Laird, 1986) was utilized oriented with the
meta-analysis on the detection of drastic heterogeneity (P ≤ 0.10). Or else, the estimation of the
pooled OR and 95% CI was conducted in virtue of fixed effect model applying the Mantel-
Haenszel method (Mantel and Haenszel, 1959). The analysis on Subgroup analyses was carried
out for investigating the distinctions in cancer types, ethnicity and sample size. Publication bias
was estimated by the asymmetry of the funnel plot. The estimation of Begg’s rank correlation test
(Begg and Mazumdar, 1994) and Egger’s linear regression test (Egger et al., 1997) was conducted
for quantative assessment on the funnel plot asymmetry (P ≤ 0.05 meant significant publication
bias). Sensitivity analyses were attained in virtue of omitting every data set, which was also
assessing its influence upon the pooled OR and 95% CI. The creation of Galbraith plots was made
6
for a graphical identification on the outliers which was also the sources of between-study
heterogeneity (Galbraith, 1988). A leave-one-out sensitivity analysis was implemented for
evaluation on the impacts exerted by each case-control research on the statistical significance of
the pooled estimation. An R workflow for meta-analysis on binary outcomes was conducted
oriented with quantitative data synthesis. The implementation of statistical analysis modules out
of the “meta” package (Schwarzer, 2007) was made. The Review Manager software was employed
to confirm the whole estimations listed above.

3. Results
3.1 Characteristics of the studies
Firstly, 318 essays and theses could be found in all four databases. The number contributed to an
in-depth power of narrow-down in virtue of the screening according to the previous inclusion and
exclusion criteria (Figure 1). There were 282 reviews, conference abstracts, meta-analyses and
irrelevant records, which had been refused after the review on the title and abstract. Furthermore,
there were 2 essays with overlapping or incomplete data sets, which were not included (Xu et al.,
2007; Vairaktaris et al., 2008). Besides, a research for hepatocellular carcinoma risk was cut out
and the reason was that the total number of control samples were made up of the patients with
hepatitis C virus-associated chronic liver disease (Okamoto et al., 2010). It is also a risky threat
for the cancer. Moreover, there were 4 researches (Jin, 2005; Zhai et al., 2007; Vairaktaris et al.,
2009; Banday et al., 2016) based on deviations removed. At length, there were altogether 29
studies ( Zhang et al., 2004; Matsumura et al., 2005; Elander et al., 2006; Kubben et al., 2006; Xu
et al., 2006; Tu et al., 2007; Woo et al., 2007; Xing et al., 2007; Zhang et al., 2008; Fu et al., 2009;
7
Ohtani et al., 2009; Xia et al., 2010; Park et al., 2011; Krishnaveni et al., 2012; Wu et al., 2012;
Chen et al., 2013; El Samanoudy et al., 2014; Guan et al., 2014; Avci et al., 2015; Eftekhary et al.,
2015; Verma et al., 2015; Zhang et al., 2015; Radunovic et al., 2016; Banday et al, 2016; Liu et
al., 2017; Felizi et al., 2018; Li et al., 2019; Wu et al., 2019; Liutkevcius et al.,2020; Abd et al.,2020;
Kiani et.al., 2020), which involved in 10,547 individual patients (composed of 4,671 cancer
patients as well as 5,876, controls) made up the retrieved parts oriented with in-depth analyses.

Fig.1 | Workflow expresses information through the steps of systematic review to the meta-analysis in this research.

8
3.2 Quantitative synthesis and subgroup analysis
Table 1 offers the summarization of the connection harbored by the rs3918242 polymorphism and
risk of digestive system cancers. Significant heterogeneity was investigated in heterozygote and
dominant models, thus making the application of, the random-effects model. When it comes to the
homozygote and recessive models, the fixed-effect model, the summary odds ratio and 95% CI in
homozygote model and recessive model reveals a significant indication of the upgraded risk [the
homozygote model: OR=1.54, 95% CI: 1.13-2.09 (Figure 2)]. Nevertheless, not only the
heterozygote model but also the dominant model could not present statistical significance
(heterozygote model: OR=1.01, 95% CI: 0.79-1.29; dominant model: OR=1.09, 95% CI: 0.84-
1.41). The degree of statistical significance still harbors material unchanged factors on condition
of being grouped by the sample size of the whole four models.
In regard of the stratified analysis of geographic areas, the pooled estimations in recessive model
were displaying a dramatic association shared by the T allele of this polymorphism and enhanced
cancer risk that was encountered by the Asian subgroup as well as non-Asian subgroup. In the
duration of the stratification in accordance with cancer types, the dramatic differences of
subgroups could be under identification. In terms of the subgroups of gastric cancer and liver
cancer, the homozygote carriers of the T allele harbored by this polymorphism expressed drastic
relevance to the doubled carcinogenic risk. Nevertheless, the researches’ quantitative synthesis on
other cancer types (Colorectal cancer, Oral and salivary gland cancer, and Esophageal cancer) did
not reveal any statistical significance.
9

Fig.2 | Forest plot of the association between the MMP9 rs3918242 polymorphism and cancer risk in the homozygote model.

3.3 Publication bias and Sensitivity analysis
The shape of funnel plots presented no obvious evidence of evident asymmetries (Figure 3),
suggesting a small likelihood of publication bias. Either Begg’s rank correlation test (homozygote
model: P=0.148; heterozygote model: P=0.838; dominant model: P=0.396; recessive model:
P=0.158) or Egger’s linear regression test (Homozygote model: P=0.556; Heterozygote model:
P=0.961; Dominant model: P=0.598; Recessive model: P=0.938) did not express any statistical
significance. Sensitivity analysis on the total four models revealed the pooled estimation has no
any substantial influence from any of the individual research (Figure 4).
Study
Fixed effect model
Random effects model
Heterogeneity: I
2
= 22%, t
2
= 0.1751, p = 0.18
Avci 2015
Banday 2016
Eftekhary 2015
EI 2014
Elander 2006
Guan 2014
Krishnaveni 2012
Kubben 2006
Liu 2017
Matsumura 2005
Ohtani 2009
Park 2011
Radunovic 2016
Tu 2007
Valraktaris 2009
Verma 2015
Woo 2007
Wu 2012
Xing 2007
Xu 2006
Zhai 2007
Zhang L 2015
Zhang Wei 2008
Zhang Xue 2004
Liutkevcius 2020
Abd 2020
Li 2019
Kiani 2020
Wu 2019
Events
1
10
3
61
0
10
34
1
0
6
2
2
3
5
0
8
2
17
0
2
0
164
4
4
4
0
0
4
13
Total
3181
54
91
40
34
97
84
38
59
47
133
84
270
53
144
84
108
155
5
104
98
338
18
128
169
73
137
201
72
263
Experimental
Events
1
8
3
16
2
92
20
3
1
5
1
6
2
1
0
8
1
8
5
1
0
173
3
7
19
0
0
1
7
Total
4054
46
142
34
21
165
6
42
42
62
156
47
237
73
140
114
143
230
20
147
94
369
7
155
584
303
130
173
100
272
Control
0.01 0.1 1 10 100
Odds Ratio OR
1.54
1.52
0.85
2.07
0.84
0.34
9.35
0.22
0.43
1.43
1.12
0.29
2.13
5.00
1.35
2.99
0.12
1.94
1.63
2.00
0.87
5.82
1.97
95%−CI
[1.13; 2.09]
[1.02; 2.26]
[0.05; 13.96]
[0.78; 5.45]
[0.16; 4.45]
[0.02; 7.06]
[2.82; 31.04]
[0.02; 2.23]
[0.02; 10.83]
[0.43; 4.78]
[0.10; 12.71]
[0.06; 1.44]
[0.34; 13.22]
[0.58; 43.35]
[0.49; 3.72]
[0.27; 33.30]
[0.01; 2.27]
[0.17; 21.73]
[0.36; 7.44]
[0.58; 6.91]
[0.29; 2.63]
[0.64; 53.24]
[0.77; 5.01]
(fixed)
100.0%
−−
1.6%
8.5%
4.6%
0.0%
2.8%
0.0%
3.1%
5.3%
2.0%
6.7%
1.9%
9.7%
2.4%
1.5%
0.0%
9.7%
1.2%
0.0%
6.9%
1.5%
0.0%
0.0%
4.0%
4.7%
10.7%
0.0%
0.0%
1.2%
10.0%
Weight
(random)
−−
100.0%
1.8%
9.7%
4.5%
0.0%
1.6%
0.0%
7.4%
2.6%
1.4%
7.3%
2.4%
4.8%
3.9%
2.9%
0.0%
9.2%
2.4%
0.0%
1.7%
2.4%
0.0%
0.0%
5.3%
7.1%
8.2%
0.0%
0.0%
2.8%
10.2%
Weight
10

Fig.3 | Funnel plot of the 29 studies included in the homozygote model of this meta-analysis.

0.1 0.2 0.5 1.0 2.0 5.0 10.0 20.0 50.0
1.5 1.0 0.5 0.0
Odds Ratio
Standard Error
11

Fig.4 | Sensitivity analysis for the homozygote model.

3.4 Heterogeneity analysis
The generation of Galbraith plots was committed for visualizing the heterogeneity which has been
identified in the heterozygote as well as dominant models. Following the removal of the outliers
Study
Fixed effect model
Omitting Avci 2015
Omitting Banday 2016
Omitting Eftekhary 2015
Omitting EI 2014
Omitting Elander 2006
Omitting Guan 2014
Omitting Krishnaveni 2012
Omitting Kubben 2006
Omitting Liu 2017
Omitting Matsumura 2005
Omitting Ohtani 2009
Omitting Park 2011
Omitting Radunovic 2016
Omitting Tu 2007
Omitting Valraktaris 2009
Omitting Verma 2015
Omitting Woo 2007
Omitting Wu 2012
Omitting Xing 2007
Omitting Xu 2006
Omitting Zhai 2007
Omitting Zhang L 2015
Omitting Zhang Wei 2008
Omitting Zhang Xue 2004
Omitting Liutkevcius 2020
Omitting Abd 2020
Omitting Li 2019
Omitting Kiani 2020
Omitting Wu 2019
0.5 1 2
Odds Ratio OR
1.54
1.55
1.49
1.57
1.54
1.57
1.54
1.29
1.61
1.56
1.55
1.55
1.67
1.52
1.49
1.54
1.56
1.52
1.54
1.64
1.53
1.54
1.54
1.54
1.52
1.62
1.54
1.54
1.49
1.49
95%−CI
[1.13; 2.09]
[1.14; 2.11]
[1.08; 2.06]
[1.15; 2.15]
[1.13; 2.09]
[1.16; 2.14]
[1.13; 2.09]
[0.93; 1.79]
[1.18; 2.20]
[1.15; 2.12]
[1.13; 2.12]
[1.14; 2.10]
[1.22; 2.29]
[1.12; 2.08]
[1.09; 2.03]
[1.13; 2.09]
[1.13; 2.15]
[1.12; 2.07]
[1.13; 2.09]
[1.20; 2.25]
[1.13; 2.09]
[1.13; 2.09]
[1.13; 2.09]
[1.12; 2.10]
[1.11; 2.08]
[1.18; 2.23]
[1.13; 2.09]
[1.13; 2.09]
[1.09; 2.03]
[1.08; 2.06]
12
marked in Galbraith plots for the heterozygote model (Figure 5) (Woo et al., 2007; Park et al.,
2011; Verma et al., 2015; Zhang et al., 2015; Radunovic et al., 2016) and the dominant model
(Figure 6) (Woo et al., 2007; Park et al., 2011; Wu et al., 2012; Verma et al., 2015; Zhang et al.,
2015; Radunovic et al., 2016), no drastic heterogeneity could be discovered. Nonetheless, the
pooled results were still featured by stability (heterozygote model, OR=1.01, 95% CI: 0.79-1.29;
dominant model, OR=1.09, 95% CI: 0.84-1.41).

Fig.5 | Galbraith plot for the heterozygote model
0 1 2 3 4 5
-4 -2 0 2 4
Inverse of standard error
Standardised treatment effect (z-score)
Verma 2015
Radunovic 2016
Zhang 2015
Woo 2007
Park 2011
13

Fig.6 | Galbraith plot for the dominant model.

4. Discussion
According to the pooled ORs and corresponding 95% CIs belonging to the homozygote model and
the recessive model, the TT carrier of the polymorphism might can grant more susceptibility to
globally-striken cancer risk oriented with the digestive system. The stratified analysis regarding
ethnicity displayed the dramatically doubled cancer risks oriented with the non-Asian population
in the heterozygote model, the dominant model as well as the recessive model. In terms of the
Asian population, the effects exerted by the T allele were established merely in the recessive model
based on the only borderline significance. Our meta-analysis’ contradiction with the previous
0 1 2 3 4 5 6
-4 -2 0 2 4
Inverse of standard error
Standardised treatment effect (z-score)
Wu 2012
Verma 2015
Radunovic 2016
Zhang 2015
Woo 2007 Park 2011
14
findings oriented with the protective role performed by the MMP9 rs3918242 polymorphism (Li
et al., 2013).
Carcinogenic mechanisms are varying in accordance with the distinct cancer types. The stratified
analyses abiding by cancer kinds were implemented for the estimation of the impacts of this
polymorphism. The pooled estimation presented the evidence of the homozygote T allele carrier
of the MMP9 rs3918242 polymorphism to enhanced cancer risk, in particular, for liver and gastric
cancers. Nevertheless, our confidence was born of the carcinogenic effects for liver cancer is under
restriction of the relatively small sample size as well as the designated restricted geographic
distribution of the selected researches.
I laid emphasis upon the heterogeneity while illustrating the conclusions of this research. Galbraith
plots were employed for identifying the source of heterogeneity in the field of the heterozygote
and dominant models. No detection was made on significant heterogeneity in those two genetic
models when the removal of the outliers was made; the pooled estimation was still of stability.
That managed to essentially strengthen our confidence in the conclusions.
The dominating strength of the meta-analysis lies in the pooled sample size, giving rise to larger
statistical power in comparison to any single research. Additionally, the methodology adopted by
this meta-analysis follows rigorous requirements (such as literature search and selection, data
extraction, statistical analysis, in addition to results interpretation). Sensitivity and publication bias
analyses shows the in-depth confirmation on the liveliness of the results. Nevertheless, despite that
holding high the PRISMA statement, this meta-analysis’ validity abides by the constraints as
follows. First, the analysis is merely made up of case-control researches as well as no cohort
researches. As the major part of the research in association with the highlighted the issue out of
15
the restricted data resource belongs to case-control researches. Future researches will see the value
of exploring cohort studies. Second, a sort of inherent limitations used in the experimental design
was authentically influencing the score out of NOS quality estimation. For another, there are some
researches which could not offer evidence to conform the standards and requirements on the
selection of controls (without history of cancer and community controls). Another reason is that,
controls could not match the cases in ages and genders, and that could impose impacts upon the
comparability of case as well as control groups. Those issues make a potential factor resulting in
a distortion of the summarized estimation. Moreover, most researches included in this meta-
analysis were born out of Asia. The limited geographic distribution of these relevant was able to
bring in several potentially biasing confounders composed of dietary habit and environmental
pollution. It could be interactive with the genetic factors. Fourth, it is a common sense that the
synergistic effects with infection with Helicobacter pylori, alcohol abuse, and other dietary risk
factors are interpreted in a thorough way for the in-depth adjusted researches when larger numbers
of detailed individual data has been integrated Fifthly, the analysis merely underlined MMP9
rs3918242 polymorphism considering that it turned out to be a dramatic SNP, is ever regarded to
harbor latent relevance to cancer risk. Nevertheless, it is certain that there may be other
polymorphisms worthy of being under investigation. Thereby, it is required that in-depth case-
control researches on the basis of large-scale population-based originated out of differential
geographic regions should validate our results.
To sum up, the promoted summary ORs oriented with the homozygote and recessive models works
as a provider of evidence which can homozygote carriers of the T alleles featured by the MMP9
rs3918242 polymorphism has relevance to the elevated risks of undergoing digestive system
malignancies, in particular, liver cancer as well as gastric cancer.
16
REFERENCES
Abd Elmaogoud Ragab Ibrahim, F., Essam Elfeky, S., Haroun, M., Abd Elrahman Ahmed, M.,
Elnaggar, M., et al. (2020). Association of matrix metalloproteinases 3 and 9 single
nucleotide polymorphisms with breast cancer risk: A case-control study. Molecular and
clinical oncology 13(1), 54–62.
Avci, N., Ture, M., Deligonul, A., Cubukcu, E., Olmez, O.F., Sahinturk, S., et al. (2015).
Association and Prognostic Significance of the Functional-1562C/T Polymorphism in the
Promoter Region of MMP-9 in Turkish Patients with Gastric Cancer. Pathology &
Oncology Research 21(4), 1243-1247.
Banday, M.Z., Sameer, A.S., Mir, A.H., Mokhdomi, T.A., Chowdri, N.A., and Haq, E. (2016).
Matrix metalloproteinase (MMP)-2,-7 and-9 promoter polymorphisms in colorectal cancer
in ethnic Kashmiri population-A case-control study and a mini review. Gene 589(1), 81-
89.
Begg, C.B., and Mazumdar, M. (1994). Operating characteristics of a rank correlation test for
publication bias. Biometrics, 1088-1101.
Chen, J., Qi, F., Huang, Y ., and Zhang, L. (2013). The study on the relationship between
polymorphism of MMP-9 and gastric cancer. Modern Preventive Medicine 40(12), 2329-
2336.
Deng, N., Zhou, H., Fan, H., & Yuan, Y . (2017). Single nucleotide polymorphisms and cancer
susceptibility. Oncotarget, 8(66), 110635–110649.
DerSimonian, R., and Laird, N. (1986). Meta-analysis in clinical trials. Control Clin Trials 7(3),
177-188.
Eftekhary, H., Ziaee, A.-A., Yazdanbod, M., Shahpanah, M., Setayeshgar, A., and Nassiri, M.
(2015). The influence of matrix metalloproteinase-2, -9, and -12 promoter polymorphisms
on Iranian patients with oesophageal squamous cell carcinoma. Wspolczesna Onkologia-
Contemporary Oncology 19(4), 300-305.
Egger, M., Smith, G.D., Schneider, M., and Minder, C. (1997). Bias in meta-analysis detected by
a simple, graphical test. BMJ 315(7109), 629-634.
El Samanoudy, A., Monir, R., Badawy, A., Ibrahim, L., Farag, K., El Baz, S., et al. (2014). Matrix
metalloproteinase-9 gene polymorphism in hepatocellular carcinoma patients with
hepatitis B and C viruses. Genetics and Molecular Research 13(3), 8025-8034.
Elander, N., Soderkvist, P., and Fransen, K. (2006). Matrix metalloproteinase (MMP)-1,-2,-3 and-
9 promoter polymorphisms in colorectal cancer. Anticancer Research 26(1B), 791-795.
Fu, Y ., Hu, H.-m., Tan, Y ., Tang, S.-j., Xiong, G., Yang, K., et al. (2009). Correlation between the
polymorphism of matrix metalloproteinase-9 and esophageal squamous cell carcinoma
17
patients in Southwest China. Acta Academiae Medicinae Militaris Tertiae 31(12), 1131-
1134.
Galbraith, R. (1988). A note on graphical presentation of estimated odds ratios from several clinical
trials. Statistics in medicine 7(8), 889-894.
Guan, X., Wang, X., Luo, H., Wu, J., Zhang, X., and Wu, J. (2014). Matrix Metalloproteinase 1, 3,
and 9 Polymorphisms and Esophageal Squamous Cell Carcinoma Risk. Medical Science
Monitor 20, 2269-2274.
Hsiao, F.-C., Yeh, Y .-H., Chen, W.-J., Chan, Y .-H., Kuo, C.-T., Wang, C.-L., et al. (2016). MMP9
Rs3918242 Polymorphism Affects Tachycardia-Induced MMP9 Expression in Cultured
Atrial-Derived Myocytes but Is Not a Risk Factor for Atrial Fibrillation among the
Taiwanese. International journal of molecular sciences 17(4), 521.
Hu, C., Weng, F., Li, L., Dai, W., Yan, J., Peng, L., et al. (2018). Association between MMP-9 -
1562 C/T polymorphism and susceptibility to digestive cancers: A meta-analysis. Gene 673,
88-94. doi: 10.1016/j.gene.2018.06.025.
Jin, X. (2005). Association of the Matrix Metalloproteinases Polymorphism with Esophageal
Squamous Cell Carcinoma and Gastric Cardiac Adenocarcinoma. MS, Hebei Medical
University.
Kiani, A., Kamankesh, M., Vaisi-Raygani, A., Moradi, M. R., et al. (2020). Activities and
polymorphisms of MMP-2 and MMP-9, smoking, diabetes and risk of prostate cancer.
Molecular biology reports 47(12), 9373–9383.
Krishnaveni, D., Bhayal, A.C., Sri Manjari, K., Vidyasagar, A., Uma Devi, M., Ramanna, M., et
al. (2012). MMP 9 Gene Promoter Polymorphism in Gastric Cancer. Indian J Clin Biochem
27(3), 259-264.
Kubben, F.J.j.M., Sier, C.F.M., Meijer, M.J.W., van den Berg, M., van der Reijden, J.J., Griffioen,
G., et al. (2006). Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer.
British Journal of Cancer 95(6), 744-751.
Li, X., Qu, L., Zhong, Y ., Zhao, Y ., Chen, H., and Lu, D. (2013). Association between promoters
polymorphisms of matrix metalloproteinases and risk of digestive cancers: a meta-analysis.
Journal of Cancer Research and Clinical Oncology 139(9), 1433-1447.
Li, W., Jia, M. X., Wang, J. H., Lu, J. L., Deng, J., Tang, J. X., & Liu, C. (2019). Association of
MMP9-1562C/T and MMP13-77A/G Polymorphisms with Non-Small Cell Lung Cancer
in Southern Chinese Population. Biomolecules 9(3), 107.
Liu, D., Guo, H., Li, Y ., Xu, X., Yang, K., and Bai, Y . (2012). Association between Polymorphisms
in the Promoter Regions of Matrix Metalloproteinases (MMPs) and Risk of Cancer
Metastasis: A Meta-Analysis. PLOS ONE 7(2), e31251.
Liu, Y ., Zheng, W., Zhang, J., and Li, B. (2017). Association between matrix metalloproteinase - 9
18
expression, gene polymorphism and risk of colorectal cancer in North China. Chinese
Journal of Experimental Surgery 34(1), 14-16.
Liutkevicius, V ., Lesauskaite, V ., Liutkeviciene, R., Vaiciulis, P., & Uloza, V . (2020). Matrix
Metalloproteinases (MMP-2,-3,-9) Gene Polymorphisms in Cases of Benign V ocal Fold
Lesions and Laryngeal Carcinoma. In vivo (Athens, Greece) 34(1), 267–274.
Mantel, N., and Haenszel, W. (1959). Statistical aspects of the analysis of data from retrospective
studies of disease. J Natl Cancer Inst 22(4), 719-748.
Matsumura, S., Oue, N., Nakayama, H., Kitadai, Y ., Yoshida, K., Yamaguchi, Y ., et al. (2005). A
single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and
invasive phenotype of gastric cancer. Journal of Cancer Research and Clinical Oncology
131(1), 19-25.
Matsuyama, Y ., Takao, S., and Aikou, T. (2002). Comparison of matrix metalloproteinase
expression between primary tumors with or without liver metastasis in pancreatic and
colorectal carcinomas. J Surg Oncol 80(2), 105-110.
Moher, D., Liberati, A., Tetzlaff, J., and Altman, D.G. (2009). Preferred reporting items for
systematic reviews and meta-analyses: the PRISMA statement. BMJ 339.
Ohtani, H., Maeda, N., and Murawaki, Y . (2009). Functional Polymorphisms in the Promoter
Regions of Matrix Metalloproteinase-2,-3,-7,-9 and TNF-alpha Genes, and the Risk of
Colorectal Neoplasm in Japanese. Yonago Acta Medica 52(1), 47-56.
Okamoto, K., Ishida, C., Ikebuchi, Y ., Mandai, M., Mimura, K., Murawaki, Y ., et al. (2010). The
Genotypes of IL-1 beta and MMP-3 are Associated with the Prognosis of HCV-related
Hepatocellular Carcinoma. Internal Medicine 49(10), 887-895. doi:
10.2169/internalmedicine.49.3268.
Park, K.S., Kim, S.J., Kim, K.H., and Kim, J.C. (2011). Clinical characteristics of TIMP2, MMP2,
and MMP9 gene polymorphisms in colorectal cancer. Journal of Gastroenterology and
Hepatology 26(2), 391-397. doi: 10.1111/j.1440-1746.2010.06504.x.
Peng, Z., Jia, J., Gong, W., Gao, X., Ma, P., Jin, Z., Fan, Y ., Li, Y ., Zhang, X. (2017). The
association of matrix metalloproteinase-9 promoter polymorphisms with gastric cancer risk:
a meta-analysis. Oncotarget, 8(58), 99024–99032.
Radunovic, M., Nikolic, N., Milenkovic, S., Tomanovic, N., Boricic, I., Dimitrijevic, M., et al.
(2016). The MMP-2 and MMP-9 promoter polymorphisms and susceptibility to salivary
gland cancer. Journal of Buon 21(3), 597-602.
Roy, R., Yang, J., and Moses, M.A. (2009). Matrix metalloproteinases as novel biomarkers and
potential therapeutic targets in human cancer. Journal of clinical oncology 27(31), 5287.
Schwarzer, G. (2007). Meta: An R package for meta-analysis. R news 7(3), 40-45.
19
Thakkinstian, A., McElduff, P., D'Este, C., Duffy, D., and Attia, J. (2005). A method for meta-
analysis of molecular association studies. Stat Med 24(9), 1291-1306. doi:
10.1002/sim.2010.
Tu, H.-F., Wu, C.-H., Kao, S.-Y ., Liu, C.-J., Liu, T.-Y ., and Lui, M.-T. (2007). Functional -1562 C-
to-T polymorphism in matrix metalloproteinase-9 (MMP-9) promoter is associated with
the risk for oral squamous cell carcinoma in younger male areca users. Journal of Oral
Pathology & Medicine 36(7), 409-414.
Vairaktaris, E., Serefoglou, Z., Avgoustidis, D., Yapijakis, C., Critselis, E., Vylliotis, A., et al.
(2009). Gene polymorphisms related to angiogenesis, inflammation and thrombosis that
influence risk for oral cancer. Oral Oncology 45(3), 247-253.
Vairaktaris, E., Vassiliou, S., Nkenke, E., Serefoglou, Z., Derka, S., Tsigris, C., et al. (2008). A
metalloproteinase-9 polymorphism which affects its expression is associated with
increased risk for oral squamous cell carcinoma. European journal of surgical oncology
34(4), 450-455.
Verma, S., Kesh, K., Gupta, A., and Swarnakar, S. (2015). An Overview of Matrix
Metalloproteinase 9 Polymorphism and Gastric Cancer Risk. Asian Pac J Cancer Prev
16(17), 7393-7400.
Woo, M., Park, K., Nam, J., and Kim, J.C. (2007). Clinical implications of matrix
metalloproteinase-1,-3,-7,-9,-12, and plasminogen activator inhibitor-1 gene
polymorphisms in colorectal cancer. Journal of Gastroenterology and Hepatology 22(7),
1064-1070.
Wu, H.D., Bai, X., Chen, D.M., Cao, H.Y ., and Qin, L. (2013). Association of genetic
polymorphisms in matrix metalloproteinase-9 and coronary artery disease in the Chinese
Han population: a case-control study. Genet Test Mol Biomarkers 17(9), 707-712.
Wu, S., Shao, L., Li, S., Zhang, F., Xie, H., Zhang, C., et al. (2012). Correlation of MMP-9 and
MMP-2 Gene SNPs with Hepatocellular Carcinoma Invasion and Metastasis. Cancer
Research on Prevention and Treatment 39(6), 683-686.
Wu, M., Tzeng, H., Wu, C., Yueh, T., Peng, Y ., Tsai, C., Wang, Y ., Ke, T., Pei, J, Chang, W., Tsai,
C., Bau, D (2019). Association of Matrix Metalloproteinase-9 rs3918242 Promoter
Genotypes With Colorectal Cancer Risk. Anticancer Res 39(12):6523-6529.
Xia, P., Chang, D., Dang, C., Lei, M., Xue, H., and Liu, Y . (2010). Association between the - 1562
C/T polymorphism in the MMP-9 promoter and phenotype of esophageal squamous cell
carcinoma in northern Chinese population. Academic Journal of Xi'an Jiaotong University
22(1), 39-43.
Xing, L.-L., Wang, Z.-N., Jiang, L., Zhang, Y ., Xu, Y .-Y ., Li, J., et al. (2007). Matrix
metalloproteinase-9-1562C > T polymorphism may increase the risk of lymphatic
metastasis of colorectal cancer. World Journal of Gastroenterology 13(34), 4626-4629.
20
Xu, E., Xia, X., Lue, B., Xing, X., Huang, Q., Ma, Y ., et al. (2007). Association of matrix
metalloproteinase-2 and-9 promoter polymorphisms with colorectal cancer in Chinese.
Molecular Carcinogenesis 46(11), 924-929.
Xu, E.P., Huang, Q., Lu, B.J., Xing, X.M., and Lai, M.D. (2006). The correlation between
polymorphisms of matrix metalloproteinase-2 and -9 genes and colorectal cancer of
Chinese patients. Chinese journal of medical genetics 23(1), 78-81.
Zhai, Y ., Qiu, W., Dong, X.J., Zhang, X.M., Xie, W.M., Zhang, H.X., et al. (2007). Functional
polymorphisms in the promoters of MMP-1, MMP-2, MMP-3, MMP-9, MMP-12 and
MMP-13 are not associated with hepatocellular carcinoma risk. Gut 56(3), 445-447.
Zhang, B., Ye, S., Herrmann, S.M., Eriksson, P., de Maat, M., Evans, A., et al. (1999). Functional
polymorphism in the regulatory region of gelatinase B gene in relation to severity of
coronary atherosclerosis. Circulation 99(14), 1788-1794.
Zhang, L., Xi, R.X., and Zhang, X.Z. (2015). Matrix metalloproteinase variants associated with
risk and clinical outcome of esophageal cancer. Genetics and Molecular Research 14(2),
4616-4624. doi: 10.4238/2015.May.4.20.
Zhang, W.-q., Zhao, J., Liu, J.-f., Hu, K.-q., Pei, Y .-x., and Zhou, Y .-a. (2008). Risk of cardiac and
gastric cancer and gene polymorphisms of matrix metalloproteinase(MMP)-9 in
northwestern Chinese population of Han nationality of China. China Journal of Modern
Medicine 18(22), 3262-3265.
Zhang, X.-M., Miao, X.-P., Xiong, P., Yu, C.-Y ., Tan, W., Qu, S.-N., et al. (2004). Association of
functional polymorphisms in matrix metalloproteinase-2 (MMP-2) and MMP-9 genes with
risk of gastric cancer in a Chinese population. Chinese Journal of Cancer 23(11), 1233-
1237.
Zhang, L., Xi, R., Zhang, X. (2015). Matrix metalloproteinase variants associated with risk and
clinical outcome of esophageal cancer. Genetics and Molecular Research 14(2), 4616-4624.
21
Table 1 | Association between the MMP9 rs3918242 polymorphism and cancer risk
Comparison Homozygote model (TT vs. CC) Heterozygote model (CT vs. CC) Dominant model (TT+CT vs. CC) Recessive model (TT vs. CT+CC)
OR (95% CI) P P h OR (95% CI) P P h OR (95% CI) P P h OR (95% CI) P P h
Overall 1.54(1.13,2.09) <0.01 0.18 1.01(0.79,1.29) 0.71 <0.01 1.09(0.84,1.41) 0.34 <0.01 1.61(1.03,2.53) <0.01 0.16
Ethnicity
Asian 1.74(1.25,2.44) 0.04 0.21 0.96(0.73,1.23) 0.94 0.03 1.05(0.76,1.145) 0.53 <0.01 1.28(1.05,1.76) 0.05 0.13
Others 0.78(0.35,1.76) 0.06 0.48 1.34(0.96,1.53) 0.23 0.28 1.28(0.87,1.86) 0.09 0.23 1.83(1.07,2.98) 0.06 0.43
Cancer Type
Colorectal Cancer 0.38(0.23,1.58) 0.21 0.67 0.78(0.54,1.17) 0.03 0.28 0.77(0.57,0.96) 0.07 0.45 0.48(0.39,1.23) 0.23 0.49
Esophageal Cancer 1.13(0.36,2.97) 0.67 0.07 1.06(0.93,1.33) 0.42 0.17 1.12(0.93,1.54) 0.27 0.13 1.08(0.88,1.55) 0.89 0.31
Gastric Cancer 1.57(1.03,1.98) 0.01 0.89 1.09(0.77,1.57) 0.36 0.08 1.15(0.86,1.35) 0.15 0.05 1.45(1.23,2.42) 0.03 0.89
Liver Cancer 3.06(1.08,10.79) 0.05 0.08 1.14(0.57,2.31) 0.75 0.47 2.14(1.25,3.43) 0.02 0.13 2.97(1.62,4.88) <0.01 0.12
Others 1.38(0.90,2.12) 0.13 0.49 1.16(0.47,2.87) 0.65 0.05 1.31(0.58,2.78) 0.43 0.02 2.72(0.83,9.93) 0.15 0.38
Ph: P values for heterogeneity.

Abstract (if available)

Abstract Meta-analysis is a suitable approach to produce a pooled estimate closest to the unknown common truth by combining the results of multiple scientific studies that address the same question. This meta-analysis was performed to quantitively verify the genetic effect of the MMP9 rs3918242 polymorphism on cancer risk of the digestive system. In total, twenty-nine studies with 4,671 cases and 5,876 controls were included by a systematic literature search within four electronic databases. R scripts were developed to measure odds ratios (ORs) and corresponding 95% confidence interval (95% CIs) to assess the impact of the polymorphism. Pooled estimates statistically revealed the significant carcinogenic effect of the MMP9 rs3918242 polymorphism homozygote genotypes on the digestive system, especially for liver and stomach. Given the statistical significance, the results suggested the MMP9 rs3918242 polymorphism homozygosity may associate with increasing risk of liver and gastric cancer.

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Creator Liu, Yina (author)

Core Title The carcinogenic effect of the MMP9 rs3918242 polymorphism on the risk of cancer of the digestive system: evidence from a meta-analysis

School Keck School of Medicine

Degree Master of Science

Degree Program Biostatistics

Degree Conferral Date 2021-05

Publication Date 05/07/2021

Defense Date 05/02/2021

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag cancer,digestive system,meta-analysis,MMP9,OAI-PMH Harvest,polymorphism

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Language English

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Advisor Li, Ming (committee chair), Marjoram, Paul (committee member), Thomas, Duncan (committee member)

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