T polymorphism and susceptibility to digestive cancers: A meta-analysis

Accepted Manuscript Association between MMP-9 −1562 C/T polymorphism and susceptibility to digestive cancers: A meta-analysis

Hu Chaoliang, Weng Fangzhong, Li Lin, Dai Wei, Yan Jun, Peng Liqing, Zhou Ruixiang PII: DOI: Reference:

S0378-1119(18)30676-0 doi:10.1016/j.gene.2018.06.025 GENE 42958

To appear in:

Gene

Received date: Revised date: Accepted date:

12 December 2017 21 April 2018 8 June 2018

Please cite this article as: Hu Chaoliang, Weng Fangzhong, Li Lin, Dai Wei, Yan Jun, Peng Liqing, Zhou Ruixiang , Association between MMP-9 −1562 C/T polymorphism and susceptibility to digestive cancers: A meta-analysis. Gene (2017), doi:10.1016/ j.gene.2018.06.025

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ACCEPTED MANUSCRIPT Association between MMP-9 -1562 C/T polymorphism and susceptibility to digestive cancers: a meta-analysis Hu Chaoliang1, Weng Fangzhong1, Li lin, Dai Wei, Yan Jun, Peng Liqing, Zhou Ruixiang* Department of Critical Care Medicine, Wuhan No.1 hospital, Wuhan, China 1 These authors co-supervised this work. * Corresponding author at: Department of Critical Care Medicine, Wuhan No.1 hospital, Wuhan, China Tel.: +86 15377051881; fax: +86 027 85332168

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E-mail address: [email protected]

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Abstract

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Purpose Matrix metalloproteinases (MMPs) play important roles in tumorigenesis. The variant in MMP-9 -1562 C/T (single nucleotide polymorphisms labled rs3918242) has been extensively evaluated as predisposing factors to digestive cancers susceptibility. However, most of these studies only contained a small number of subjects and

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they showed conflicting results. Therefore, to elucidate these associations, we carried out a large-scale meta-analysis to provide this accurately comprehensive synopsis of case-control studies. Methods

A comprehensive literature search was conducted in EMBASE, OVID, Medline, China National

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Knowledge Internet and Wanfang for relevant data published between Jan 2000 and Mar 2018. Overall and stratified analyses based on the cancer types, ethnicity and source of control were carried out. Odds ratios (ORs) correspondent to 95% confidence intervals (95%CIs) were calculated to evaluate the genetic correlation between the variant and digestive cancer susceptibility. Review Manager 5.2 and Stata 12.0 were used for statistical

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analysis. Results Twenty studies containing 3,201 digestive cancer patients and 4,301 matched-controls were screened out.

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The overall results suggested that MMP-9 -1562 C/T polymorphism increased the susceptibility to digestive cancers under homozygote and recessive models (homozygote, OR=1.35, 95%CI 1.00–1.82, P=0.05; recessive, OR=1.42, 95%CI 1.07–1.88, P=0.02). Furthermore, in the subgroup analysis based on the source of control, similar conclusions were obtained in the population-based control subgroup (homozygote, OR=1.63, 95%CI

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1.16–2.27, P=0.004; recessive, OR=1.67, 95%CI 1.22–2.28, P=0.001), but not in the hospital-based control. In subgroup analyses based on cancer types and ethnicity, no association was observed. Conclusions Our meta-analysis suggested that MMP-9 −1562 C/T polymorphism might be related to the digestive

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cancer susceptibility. Evidence with adequate sample size is needed.

Keywords Meta-analysis, Digestive cancer susceptibility, Matrix metalloproteinase-9 (MMP-9), Polymorphism

1. Introduction Digestive cancer, composed of the digestive tract cancer and accessory organs cancer, are rampant around the world. In the USA, the estimated number of newly occurrent cases is 310,440 in 2017, and 157,700 patients will die of it. (Siegel et al., 2017). According to 2015 cancer statistics for China, gastric, liver as well as esophagus cancers were the commonest types, which dominate in cancer-related death(Chen et al., 2016). The carcinogenesis and progression of digestive cancer are a complicated process result of the intricate interactions between environmental and genetic factors. Matrix metalloproteases (MMPs) are a zinc-dependent endopeptidases family, which can contribute to

ACCEPTED MANUSCRIPT regulating cellular micro-environment. Indeed, protease and MMPs are necessary to remodel extracellular matrix(ECM, considered as the barrier in cellular invasion ) during the tumor progression(Rollin et al., 2007). The MMP9 gene (also knows as CLG4B, GELB, MANDP2, MMP-9 ) is located on human chromosome 20q11.2–q13. It can encode type IV collagenase, which can degrade type IV collagen, type V collagen, elastin as well as proteoglycan core protein and promote the migration of vascular smooth muscle cells(Gum et al., 1996). Accumulating reports have demonstrated that genetic polymorphism is associated with cancer susceptibility. Numerous studies have shown that the polymorphism in MMP-9 is related to the occurrence of cancer. However, those findings were inconclusive or controversial due to the relatively insufficient sample size. So we conducted this meta-analysis to identify the relationship between MMP-9 -1562 C/T polymorphism and digestive cancer

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susceptibility.

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2. Materials and methods

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2.1 Search strategy

Utilizing the following key items："MMP", "metalloproteinase", "polymorphism", "mutation", "variant", "risk",

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"susceptibility", and "cancer", "tumor", "carcinoma", we searched in EMBASE, OVID, Medline, China National Knowledge Internet and Wanfang , found all the relevant studies on the connection between MMP-9 rs3918242 polymorphism and digestive cancer susceptibility (dating from Jan 2000 to Mar 2018). The reference sections of

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these selected papers were also screened manually to find additional data.

2.2. Study selection

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Studies eligible for evaluation in this current meta-analysis should have satisfied all the following enrollment criteria: (1) evaluating MMP-9 -1562 C/T polymorphism and digestive cancer susceptibility; (2) case-control

(ORs) with 95% CIs.

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studies; (3) including information about available genotype frequency; and (4) results presented as odds ratios

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2.3. Data extraction and quality assessment

Two authors (Chaoliang Hu, Fangzhong Weng) independently extracted all the available data. Disagreements were solved by discussion with the third author (RuiXiang Zhou) until a consensus were achieved. Data including

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the first author, year of publication, the numbers of samples in cases and controls, genotyping methods, MMP-9 genotype distribution ,source of control (hospital-based or population-based case-control studies), and ethnicity of study population (Asian, European and African) were extracted. Quality assessment based on Newcastle–Ottawa Scale (NOS) grading system was performed by two authors, and the third author was involved if there existed any disagreement.

2.4. Statistical analysis

Pooled ORs with associated 95% CIs were applied to measure the power of the link between the variant and digestive cancers susceptibility. We calculated four genetic contrasts: homozygote comparison (TT vs CC), heterozygote comparison (CT vs CC), dominant (TT/CT vs CC) and recessive (TT vs CT/CC) genetic model comparison. Statistical heterogeneity was measured by the Q test. When P < 0.10, it was considered to be

ACCEPTED MANUSCRIPT statistically significant, and a random effect model was utilized to estimate the summarized ORs. Otherwise, a fixed effect model was utilized. The statistical significance of the pooled OR was measured by a Z-test, and P value < 0.05 was considered to be statistically significant. For each comparison, stratified analyses by cancer type, ethnicity and source of control were performed. Begg’s funnel plot and Egger’s test were conducted to examine the underlying publication bias. We also omitted one study at a time and calculated the pooled ORs (95% CIs) of the remaining studies for sensitivity analysis. All statistical analysis were done with Review Manager software (Version 5.2 ) and STATA software (Version 12.0 ), using two sided P values.

The false-positive report probability (FPRP) was calculated to evaluate the

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significant findings. We calculated FPRP from the observed P value, statistical power, and prior probability by using the FPRP calculation spreadsheet and set 0.2 as an FPRP threshold.

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Trial sequential analysis (TSA) was performed to investigate the relevance of polymorphism with cancer susceptibility. After adopting the risks of 5% for type I error and 20% for type II error, the required information

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size was calculated, and TSA monitoring boundaries were built.

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3. Results 3.1. Study location and selection

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A total of 128 records were related to keywords. 75 studies were apparently irrelevant, 5 studies were excluded because they were systematic reviews, and 21 studies were not accepted because they were not for cancer research (18 studies) or polymorphism (3 articles). Among the remaining 27 publications, 6 articles focused on other different genes; 2 articles used the same populations, thus we excluded one of them. Overall, 20 studies concerning

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3.2. Study characteristics

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MMP-9 -1562 C/T variant and the susceptibility of digestive cancers were available (Fig. 1).

Twenty published studies, which met all the criteria, were chosen for our study. The characteristics of the 20 studies were shown in Table1. The 20 case–control studies contained 3,201 cancer patients and 4,301 control

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subjects with regard to the MMP-9 -1562 C/T polymorphism; 3 of which were esophageal cancer, 6 were gastric cancer, 4 were hepatocellular cancer and 7 were colorectal cancer; in the subgroup of ethnicity, 17 took place in Asians, 2 in Europeans, and only one in Africans. There were 15 studies performed based on population-based

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control, and 5 on hospital-based controls, respectively. Among the 20 studies, the summarized quality score was from 6 to 8, which suggested that the evidence had a good quality.

3.3. Quantitative synthesis

The results of our meta-analysis concerning the correlation between MMP-9 -1562 C/T variant and digestive cancer susceptibility were summarized in Table 2. Our meta-analysis of 20 studies identified significant association between the rs3918242 gene variant and digestive cancer susceptibility in comparisons of homozygote and recessive models (homozygote, OR=1.35, 95%CI 1.00–1.82, P = 0.05; recessive, OR=1.42, 95%CI 1.07–1.88, P = 0.02) (Fig. 2,3). In the subgroup analysis based on the source of control, similar conclusions were obtained in the population-based control subgroup (homozygote, OR=1.63, 95%CI 1.16–2.27, P=0.004; recessive, OR=1.67, 95%CI 1.22–2.28, P = 0.001), but not in the hospital-based control. In the subgroup analyses based on cancer

ACCEPTED MANUSCRIPT types and ethnicity, no correlation was demonstrated between rs3918242 gene variant and digestive cancer susceptibility. The FPRP values for significant findings at different prior probability levels are shown in Table 3. For a prior probability of 0.1, the statistical power to detect an odds ratio of 1.5 (or its reciprocal, 0.67), the FPRP values were 0.166 under the recessive model, with an increased risk of digestive cancers. Positive association was observed in the subgroups of source of control. The results suggested that these significant associations were noteworthy.

3.4. Sensitivity analysis and publication bias

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We omitted one study at a time and calculated the pooled ORs of the remaining studies and found that the significance of pooled ORs was stable and reliable, indicating no bias was present. Begg’s funnel plot and

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Egger’s test were conducted to calculate the publication bias of the literature, and no bias was found in our

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meta-analysis ( P = 0.903 for CT vs CC) (Fig. 4).

3.5. Trial sequential analysis (TSA)

Fifteen trials based on population-based control (5,784 subjects) were used to investigate the relevance of

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MMP-9 polymorphism with cancer susceptibility. Using the TSA, the required information size is 12,484 subjects to demonstrate the issue (Fig. 5). The cumulative Z-curve crossed with TSA monitoring boundary, confirming that MMP-9 1562 C/T polymorphism is associated with an increased digestive cancer risk and further relevant trials are

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unnecessary.

4. Discussion

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We conduct this meta-analysis to shed light upon the role of single-nucleotide polymorphisms (SNPs) at MMP-9-1562 C/T genotypes in digestive cancer. MMP-9 gene variant may modulate the expression and activity

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levels of the enzyme, which contributes to degrading and invading ECM, thus resulting in the cancer development. For rs3918242 gene variant, it had been shown that the "T" allele had a higher promoter activity compared with the "C" allele, and then it also led to the loss of binding to the repressor protein and thus promoting transcription (Zhang et al., 1999). In some previous literature, positive association has been indicated between this variant and

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digestive cancers (Matsumura et al., 2005; Samanoudy et al., 2014; Banday et al., 2016). However, such findings were not in compliance with the study of Zhang et al., who carried out a meta-analysis. They found no association in the overall analysis between the variant genotypes of MMP-9 -1562 C/T and cancer susceptibility (Zhang et

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al., 2012). However, in the stratified analyses by cancer type, a decreased risk was found between MMP-9 -1562 C/T polymorphism and colorectal cancer risk in the allelic contrast. Because there were only 4 studies focusing on the SNP and colorectal cancer, and several novel case-control studies have been published in recent years, we were able to identify some different conclusions in this pooled analysis. We also calculate FPRP to evaluate the significant findings and use TSA to investigate the relevance. In this meta-analysis, we retrieved 20 studies that included 3,201 cases and 4,301 controls to assess the relationship between the rs3918242 gene variant and digestive cancers. Our overall results support that the variant had a significant association with increased digestive cancers in homozygote comparison (TT vs CC) and recessive genetic model (TT vs TC+CC), but other genotypes were not associated with digestive cancers. Furthermore, in the stratified analysis based on the source of control, similar results were obtained in the population-based control subgroup but not in the hospital-based control. Considering that ethnic background may affect the results of relative genomic research, we carried out a subgroup analysis by ethnicity. Three subgroups were included, "European", "Asian" and "African", the results suggested no

ACCEPTED MANUSCRIPT apparent relationship among these populations. Only one of the studies we had included was conducted among Africans, however, the results were still the same with or without this study. Subgroup analysis based on cancer types showed no significant correlation between this polymorphism and digestive cancers. Three following factors can account for these outcomes. Firstly, it is generally recognized that cancer is a multifactorial disease resulted from a variety of factors, which include inherited and environmental interactions, toxin, radiation, infection and some lifestyle factors such as diet, drinking, smoking and so on, all of these may have effect on the susceptibility of cancer, so cancer susceptibility may not be affected by a single factor (Pharoah et al, 2004). Secondly, positive results may be easily published compared with negative consequences. As a result, the number of included studies and samples was relatively small and might cause potential publication bias. Also, it may take a relatively longer

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time to be issued and lead to time-lag bias(Ioannidis, 1998). Thirdly, the variant may result in cancers at a particular locus, but multiple genic or environmental factors may play a predominant role in the occurrence or

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metastasis of cancers, which make it impossible to observe the effect of polymorphism.

The present meta-analysis has several limitations. Firstly, for comprehensive analysis, especially for specific

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subgroups of analysis, the qualified studies obtained in our analysis were relatively small, so we should be cautious when explaining the results of our analysis. Secondly, our research was primarily based on unadjusted estimates. Therefore, if possible, more accurate analyses should be carried out, including individual information (such as

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cancer stage, age and sex). Thirdly, we only analyzed studies from part of the population, so future research needs to include more ethnic groups. Still, some of the key advantages of our pooled analysis should be recognized. First of all, in this paper, a large number of cases and controls have been extracted, thus greatly improved the statistical

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power of the analysis. Second, the quality of the case–control studies included in this analysis was mainly good and no evidence of publication bias was found. Third, all the studies listed in this meta-analysis desirably conformed to our selection criteria.

In conclusion, our meta-analysis demonstrated the fact that single-nucleotide polymorphisms (SNPs) at

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MMP-9-1562 C/T might be associated with digestive cancer susceptibility. Identification of the variant will be helpful for the prevention, diagnosis and treatment of digestive cancers, but prospective randomized controlled

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Zhang, B., Ye, S., Herrmann, S., M., Eriksson, P., Maat, M., Evans, A., Arveiler, D., Luc, G., Cambien, F., Hamsten, A., Watkins, H. and Henney, A.M., 1999. Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis.

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Flow chart of the identified studies

Fig. 2.

Forest plot of MMP9 -1562 C/T polymorphism in digestive cancers risk under homozygous model

Fig. 3.

Forest plot of MMP9 -1562 C/T polymorphism in digestive cancers risk under recessive model

Fig. 4.

Funnel plot analysis to detect publication bias (CT vs CC: t=0.12, P= 0.903)

Fig. 5.

Trial sequential analysis for MMP9 -1562 C/T polymorphism under the allele contrast model.

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Fig. 1.

ACCEPTED MANUSCRIPT Abbreviations MMP, matrix metalloproteinase; SNP, single nucleotide polymorphism; OR, odds ratio; CI, confidence interval; ECM, extracellular matrix; PCR-RFLP, polymerase chain reaction-restriction fragment length polymorphism; PCC, population-based case–control; HCC, hospital-based case–control; FPRP, false-positive report probability; TSA,

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trial sequential analysis.

ACCEPTED MANUSCRIPT Table 1

Author

Year

Design

Ethnicity

Cancer type

Genotyping method

Controls

Quality Score

Avci

2015

PCC

Asian

Gastric cancer

PCR-RFLP

79

65

7

Banday

2016

PCC

Asian

Colorectal cancer

PCR-RFLP

142

184

7

Eftekhary

2015

PCC

Asian

Esophageal cancer

PCR-RFLP

68

60

7

Elander

2006

PCC

European

Colorectal cancer

PCR-DHPLC or PCR-RFLP

127

208

7

Guan

2014

PCC

Asian

Esophageal cancer

PCR-RFLP

132

132

8

Krishnaveni

2012

PCC

Asian

Gastric cancer

PCR

132

132

8

Kubben

2006

PCC

European

Gastric cancer

PCR-RFLP

79

169

7

Lee

2013

HCC

Asian

Gastric cancer

PCR-RFLP

263

354

6

Matsumura

2005

HCC

Asian

Gastric cancer

PCR-RFLP

177

224

6

Ohtani

2009

HCC

Asian

Colorectal cancer

PCR-RFLP

119

67

7

Okamoto

2005

PCC

Asian

Hepatocellular cancer

PCR-RFLP

92

170

6

Okamoto

2010

HCC

Asian

Hepatocellular cancer

PCR-RFLP

95

83

6

Park

2011

PCC

Asian

Colorectal cancer

PCR-RFLP

333

318

7

Samanoudy

2014

PCC

African

Hepatocellular cancer

PCR-RFLP

133

60

7

Woo

2007

PCC

Asian

Colorectal cancer

PCR-RFLP

185

304

7

Xia

2010

PCC

Asian

Esophageal cancer

PCR-RFLP

123

192

7

Xing

2007

HCC

Asian

Colorectal cancer

PCR-RFLP

137

199

8

Xu

2007

PCC

Asian

Colorectal cancer

PCR-DHPLC or PCR-RFLP

125

126

7

Zhang

2004

PCC

Asian

Gastric cancer

PCR-DHPLC and PCR-RFLP

228

774

7

Zhai

2006

PCC

Hepatocellular cancer

DNA sequencing

432

480

7

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HCC hospital-based case–control; PCC population-based case–control

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Cases

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Characteristics of studies included in the meta-analysis

ACCEPTED MANUSCRIPT Table 2 Stratified analyses of the MMP-9 polymorphism and digestive cancer risk. TT vs CC Subgroup Total

na

CT vs CC

TT/CT vs CC

TT vs CT/CC

Case/control OR(95%CI)

Pb

OR(95%CI)

Pb

OR(95%CI)

Pb

OR(95%CI)

Pb

20

3201/4301

1.35 [1.00, 1.82]

0.05

0.95 [0.85, 1.06]

0.37

0.98 [0.88, 1.09]

0.65

1.42 [1.07, 1.88]

0.02

Esophageal

3

323/384

1.62 [0.76, 3.48]

0.21

1.14 [0.81, 1.62]

0.45

1.21 [0.87, 1.68]

0.27

1.57 [0.74, 3.34]

0.24

Gastric

6

958/1718

1.34 [0.83, 2.17]

0.23

0.99 [0.82, 1.19]

0.88

1.01 [0.84, 1.21]

0.92

1.44 [0.92, 2.24]

0.11

Hepatocellular

4

752/793

1.83 [0.95, 3.55]

0.07

0.88 [0.69, 1.12]

0.31

0.94 [0.74, 1.19]

0.59

1.29 [0.67, 2.47]

0.45

Colorectal

7

1168/1406

0.94 [0.51, 1.72]

0.83

0.94 [0.69, 1.27]

0.68

0.93 [0.69, 1.26]

0.65

0.90 [0.49, 1.66]

0.74

Asian

17

2862/3864

1.27 [0.91, 1.77]

0.17

0.94 [0.84, 1.06]

0.30

0.96 [0.84, 1.11]

0.60

1.30 [0.95, 1.79]

0.11

European

2

206/377

0.51 [0.08, 3.15]

0.47

1.05 [0.70, 1.57]

0.81

African

1

133/60

2.35 [1.09, 5.11]

0.03

1.02 [0.48, 2.16]

0.96

PCC

15

2410/3374

1.63 [1.16, 2.27] 0.004

0.96 [0.84, 1.09]

0.51

HCC

5

791/927

0.61 [0.30, 1.25]

0.93 [0.74, 1.16]

0.50

PT

Cancer types

HCC hospital-based case–control; PCC population-based case–control a Number of comparisons

AC

CE

PT E

D

1.02 [0.68, 1.51]

0.93

0.52 [0.08, 3.15]

0.47

1.57 [0.81, 3.03]

0.18

2.33 [1.20, 4.54]

0.01

1.00 [0.89, 1.13]

0.97

1.67 [1.22, 2.28] 0.001

0.90 [0.72, 1.12]

0.33

0.64 [0.31, 1.29]

SC

MA

b P value of Q-test for heterogneity test

NU

Source of control

0.18

RI

Ethnicities

0.21

ACCEPTED MANUSCRIPT Table 3 False-positive report probability values for associations between MMP-9 -1562 C/T polymorphism and susceptibility to digestive cancers. Statistical

Prior probability

Group

Genotype

Odds ratio (95% CI)

P-valuea

powerb

0.25

0.1

0.01

0.001

0.0001

0.00001

Total

TT vs CC

1.35 [1.00, 1.82]

0.05

0.755

0.163

0.368

0.865

0.985

0.998

1.000

TT vs CT/CC

1.42 [1.07, 1.88]

0.02

0.649

0.062

0.166

0.686

0.957

0.995

1.000

TT vs CC

1.63 [1.16, 2.27]

0.004

0.311

0.036

0.100

0.549

0.925

0.992

0.999

TT vs CT/CC

1.67 [1.22, 2.28]

0.001

0.250

0.015

0.043

0.331

0.833

0.98

0.998

PCC

PT

CI confidence interval; OR odds ratio a P-value of Q-test for heterogneity test

AC

CE

PT E

D

MA

NU

SC

RI

b Statistical power was calculated using the number of observations in the subgroup and the OR and P values in this table

ACCEPTED MANUSCRIPT Highlights Meta-analysis of MMP-9 polymorphism and digestive cancers susceptibility.

2.

Provides a systematic summary of the last 20 years of research findings.

3.

20 studies with 3,201 cases and 4,301 controls were included.

4.

MMP-9 −1562 C/T polymorphism might increase digestive cancers susceptibility.

AC

CE

PT E

D

MA

NU

SC

RI

PT

1.

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5