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Clinical Cancer Research 13, 2614-2620, May 1, 2007. doi: 10.1158/1078-0432.CCR-06-1187
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

Matrix Metalloproteinase Polymorphisms Are Associated with Bladder Cancer Invasiveness

A. Karim Kader1,2, Jun Liu1, Lina Shao1, Colin P. Dinney2, Jie Lin1, Yunfei Wang1, Jian Gu1, H. Barton Grossman2 and Xifeng Wu1

Authors' Affiliations: Departments of 1 Epidemiology and 2 Urology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Xifeng Wu, Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Unit 1340, 1155 Pressler Boulevard, Houston, TX 77030. E-mail: xwu{at}mdanderson.org.


   Abstract
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 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Purpose: Matrix metalloproteinases (MMP) promote tumor invasion and alter microenvironment. MMP levels are elevated in bladder cancer patients correlating with more advanced stage. We tested whether polymorphisms in MMP genes modify the risk of bladder cancer invasiveness and whether smoke exposure modifies this risk.

Experimental Design: Using a case-only study, we examined the association of 11 single-nucleotide polymorphisms and one microsatellite polymorphism in MMP genes MMP1, MMP2, MMP3, MMP8, MMP9, and MMP12 with the risk of invasive bladder cancer in 243 Caucasian patients with muscle invasive compared with 315 Caucasian patients with superficial disease.

Results: The MMP9 microsatellite ≥24 CA repeat and MMP12 –82 G alleles were associated with a higher risk of bladder cancer invasiveness [odds ratio (OR), 3.10; 95% confidence interval (95% CI) 1.17-8.23 and OR, 1.50; 95% CI, 1.00-2.28, respectively]. Ever smokers with the MMP9 ≥24 CA repeat allele had a 5.16-fold (95% CI, 1.56-17.1) increased risk of invasiveness compared with wild-type never smokers. Ever smokers with the MMP12 G allele also had an increased risk of bladder cancer invasiveness (OR, 2.32; 95% CI, 1.30-4.12).

Conclusions: Our results suggest that genetic changes in MMPs are associated with the development of invasive bladder cancer.

Bladder cancer is the second most common urologic malignancy, with 61,000 new cases and 13,000 deaths from bladder cancer expected in 2006 in the United States alone (1). Seventy-five percent of patients with bladder cancer present with superficial disease that is confined to the urothelium and lamina propria, the remaining 25% present with muscle-invasive disease. Furthermore, disease recurs in up to 80% of the patients with originally superficial disease, but in 20% of these recurrences, this consists of muscle invasive disease that is associated with a heightened risk of metastases and death. Despite the fact that superficial disease can progress to muscle-invasive disease, the vast majority of cases of muscle-invasive disease are found at initial presentation in patients with bladder cancer (2). In keeping with this, there is growing evidence of the divergent biology that exists between the invasive and superficial forms of the disease (3, 4).

Matrix metalloproteinases (MMP) are a family of zinc-dependent enzymes that are considered to have an important cellular regulatory function by degrading the surrounding stroma, cytokines, and even membrane-bound receptors. Because of their diverse effects on the cellular microenvironment, MMPs are believed to play a substantial role in the development of a variety of inflammatory, neurodegenerative, and malignant diseases (5–9). They may foster cancer development by stimulating cellular proliferation, promoting angiogenesis, or promoting invasion and metastases (8, 10). Not surprisingly, therefore, elevated levels of MMPs have been detected in the serum and urine of patients with many different types of cancer, including cancer of the bladder, breast, lung, colon, and head and neck as well as melanoma (11). Because of the high levels of MMP1, MMP2, MMP3, and MMP9 in the urine, it is believed that they may have a role in the pathogenesis of bladder cancer and have also been advocated as tumor markers (12, 13).

Polymorphisms represent natural variations of the genetic code in the population. The most common polymorphisms are single-nucleotide polymorphisms (SNP). Other more rare polymorphisms, such as microsatellite repeats, may also have functional consequences (14). Polymorphisms in the promoter region of a gene, such as the 2G allele of MMP1 –1607, the G allele of MMP2 –1575, the 5A allele of MMP3 –1612, the –1562 T and the ≥24 CA repeat alleles of MMP9, and the A allele of the MMP12 –82, examined in this analysis can lead to increased gene expression (15). SNPs in the coding region may lead to an amino acid change that may alter protein function. It must however be recognized that the functional significance of these genetic variations may differ depending on the organ system studied. Regardless, given their potential role on expression and phenotype, polymorphisms may account for the differences seen in susceptibility to and the outcome from a given disease (16).

Smoking is the most significant risk factor for the development of bladder cancer, with smokers having three times the risk of bladder cancer compared with nonsmokers (17). This risk is greatest for patients with advanced stage, invasive disease (18). Despite this, not all smokers go on to develop bladder cancer. Therefore, there may be genetic factors that predispose some smokers to be at heightened risk for the development of invasive bladder cancer.

Associations between MMP polymorphisms and cancer risk have been found in the setting of a variety of different tumors, including melanoma and breast, ovarian, lung, and colorectal tumors (19–23). To our knowledge, however, an association between any of the MMP polymorphisms with the risk of bladder cancer invasiveness has not been explored.

In this study, we used a candidate gene approach to perform an analysis to identify the possible association of 12 polymorphisms in six different MMPs with the risk of invasive compared with superficial bladder cancer and to investigate the possible modulating effect of smoking on these associations.


   Materials and Methods
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Results
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Study population. The bladder cancer patients in this analysis were enrolled from an on-going case-control study of bladder cancer, which started patient recruitment in 1999. All enrolled patients were incident cases of histologically confirmed invasive or superficial bladder cancer and were recruited from the urology and genitourinary clinics at The University of Texas M. D. Anderson Cancer Center and The Scott Department of Urology at The Baylor College of Medicine. The vast majority of patients are from Houston, Texas and its seven surrounding counties and were referred to M. D. Anderson by local physicians. As M. D. Anderson is a large referral center, local physicians tend to refer advanced cases, and thus, advanced cases are highly represented in this study population. The participation rate was ~92%, and blood samples were available for all subjects. Ethnicity was based on self-report and categorized as Caucasian, African American, Hispanic, Asian, Native Indian, and other. However, as 90% of the patients were Caucasians, this study was limited to this population.

Trained M. D. Anderson staff interviewers administered an epidemiologic questionnaire to study participants to collect data on demographic characteristics, smoking history, occupation history, and other lifestyle factors. At the end of the interview, a 40-mL blood sample was drawn into coded tubes. All patients provided written informed consent. The M. D. Anderson Cancer Center and The Baylor College of Medicine institutional review boards approved the protocol.

Genotyping. Genomic DNA was first isolated from peripheral blood lymphocytes by proteinase K digestion followed by isopropanol extraction and ethanol precipitation; the sample was then coded and genotyped. All of the polymorphisms, except for the MMP9 –1562 and the MMP9 microsatellite polymorphisms, were determined using Taqman real-time PCR. The primer and probe sequences were either obtained from the National Cancer Institute's SNP500 database or designed using Primer Express software (Applied Biosystems) and can be found in Supplementary Table S1. The probes were labeled fluorescently with either FAM or VIC on the 5' end and a nonfluorescent minor groove binder quencher on the 3' end (Applied Biosystems). Typical amplification mixes (5 µL) contained sample DNA (5 ng), 1x Taqman buffer A, 200 µmol/L deoxynucleotide triphosphates, 5 mmol MgCl2, 0.65 unit of AmpliTaq Gold, 900 nmol/L each primer, and 200 nmol/L each probe. The thermal cycling conditions consisted of one cycle for 10 min at 95°C, 40 cycles for 15 s at 95°C, and one cycle for 1 min at 60°C. SDS version 2.1 software (Applied Biosystems) was used to analyze end-point fluorescence. In our laboratory, strict quality control procedures are implemented to ensure high genotyping accuracy. A water control, internal controls, and previously genotyped samples were included in each plate with 100% concordance. Genotyping for MMP9 –1562 was done as described previously using PCR-RFLP (19). The MMP9 microsatellite polymorphism was genotyped using capillary electrophoresis of PCR-amplified products done using a 6-FAM fluoresceinated forward-labeled primer, as described by Fiotti et al. (24).

Statistical analyses. A {chi}2 analysis was used to assess patient characteristics by genotype. The Student's t test (two sided) was used to test for differences between the different groups for continuous variables. Unconditional logistical regression analysis was performed to assess the risk associated with the various polymorphisms. Odds ratios (ORs) were calculated as an estimate of relative risk. All reported ORs were adjusted for age, sex, and smoking status. For the smoking-stratified analyses, subjects who had smoked at least 100 cigarettes in their lifetimes were defined as ever smokers. Participants who had quit smoking at least 1 year before the study began were categorized as former smokers.

For the MMP9 microsatellite data, the allele was dichotomized, such that <24 CA repeats were considered to indicate the wild-type allele, and ≥24 CA repeats were considered to indicate the variant allele. Combined analysis was done on polymorphisms that in our previous studies were shown to have relatively low linkage (D' < 0.6). Groups were divided into tertiles based on the number of patients in the nonstratified group. Individuals with less than three alleles were used as the reference group, and the two test groups consisted of individuals with four to five alleles and individuals with more than six alleles. Multivariate logistic regression analysis was done where appropriate to control for possible confounders by age, sex, and smoking status. Statistical analysis was done using Stata v8.0 software (Stata Corp.).

Regarding statistical power, our study had sufficient power to detect the main effect. Given the variant genotype frequencies, the sample size and, the ratio of invasive to superficial patients, the power to detect an OR of 2.0 reached 0.79 to 0.98 for main effect of MMP SNPs (except MMP9 A2V).


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
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Characteristics of subjects. The characteristics of the study subjects are summarized in Table 1 . Briefly, study subjects consisted of 243 Caucasian patients with invasive bladder cancer and 315 Caucasian patients with superficial bladder cancer. A similar breakdown of men and women (~76 ± 1% men and 23 ± 1% women) was noted between the two groups (P = 0.80 and 0.70 for invasive and superficial disease, respectively). Age in patients with invasive and superficial disease was also similar (mean, 64.7 and 63.6 years, respectively; P = 0.23). In contrast, there was a statistically significant difference between the two groups with respect to smoking status, in that there was a higher percentage of never smokers among the patients with superficial disease (29.8% versus 21.4%), and that there was a higher percentage of ever smokers among the patients with invasive disease (78.6% versus 70.2%; P = 0.02).


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  		Table 1. Selected characteristics of study participants who provided blood samples for genotyping

 
Genotypes and invasive bladder cancer risk. Table 2 summarizes the association of the various polymorphisms on the risk of invasive as opposed to superficial bladder cancer. The ≥24 CA repeat allele of the MMP9 microsatellite polymorphism was associated with a 3-fold higher risk of invasiveness [OR, 3.10; 95% confidence interval (95% CI), 1.17-8.23]. A similar association was seen for the G allele of the MMP12 –82 SNP, with an increased risk for the AG genotype (OR, 1.38; 95% CI, 0.90-2.12), and GG genotype (OR, 4.82; 95% CI, 0.97-23.90; Ptrend = 0.022) and the GA + GG combination (OR, 1.50; 95% CI, 1.00-2.28).


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  		Table 2. Comparison of MMP genotype in muscle-invasive versus superficial bladder cancer patients

 
Joint effects of smoking and MMP polymorphisms. We examined the joint effect of smoking and MMP polymorphisms (Table 3 ). Significant joint effects between smoking and MMP9 mircrosatellite and MMP12 –82 genotypes were observed. Compared with never smoker with the <24 repeat allele of the MMP9 microsatellite polymorphism, smokers with ≥24 CA repeat allele were at 5.16-fold increased risk of invasiveness (95% CI, 1.56-17.1). Furthermore, ever smokers with the G allele of the MMP12 –82 SNP had a 2.32-fold increased risk of invasiveness (95% CI, 1.30-4.12) compared with never smokers with the A allele. However, none of the interaction tests done were statistically significant.


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  		Table 3. Joint effect of genotype and smoking status on muscle-invasive versus superficial bladder cancer risk

 
Effect of smoke stratification on associations. Smoking-stratified analysis showed significant effects only in former smokers (Supplementary Table S2). The following alleles had a protective effect on bladder cancer invasiveness risk in former smokers: the 2G allele of the MMP1 –1607 SNP (2G2G genotype: OR, 0.48; 95% CI, 0.23-0.98; Ptrend = 0.044), the 5A allele of the MMP3 –1612 SNP (5A5A genotype: OR, 0.49; 95% CI, 0.25-0.96; Ptrend = 0.037), and the A allele of the MMP 8 K87E SNP (AA and GA genotype combination: OR, 0.56; 95% CI, 0.32-0.98). In combined analysis, the protective effect increased with an increasing number of alleles (Supplementary Table S3). That is, those with four to five alleles had a 46% lower risk of invasive disease compared with patients with superficial cases (OR, 0.54; 95% CI, 0.27-1.07), whereas those with more than six alleles had a 64% lower risk (OR, 0.36; 95% CI, 0.18-0.72; Ptrend = 0.003).


   Discussion
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 Materials and Methods
 Results
 Discussion
References
 
To our knowledge, this is the first study examining MMP polymorphisms and their association with the risk of invasive bladder cancer. In this study, the MMP12 –82 SNP and MMP9 microsatellite polymorphism were associated with an increased risk of invasive bladder cancer compared with superficial bladder cancer particularly when coupled with smoking exposure. We further observed that certain MMP alleles alone and in combination might be associated with a protective effect against invasive bladder cancer in former smokers. This contributes to a growing body of literature suggesting that the biology of invasive and superficial bladder cancer is different (3, 4).

MMPs are a class of proteases that are believed to contribute significantly and uniquely to the tumor microenvironment, which provides the elements needed for advanced tumor growth (i.e., cytokines, loss of contact inhibition, angiogenesis, and invasion; ref. 25). MMP9 and MMP12 may be of particular relevance in this regard. MMP9 is thought to be an important player in MMP-mediated invasion. It breaks down type IV collagen, a key constituent of the basement membrane, which is breached in invasive bladder cancer (10). In keeping with this, MMP9 has been detected in the urine of patients with bladder cancer but not in normal controls. Furthermore, the levels of MMP9 correlate with the stage and grade of bladder cancer, with elevated levels noted predominantly in the urine of patients with muscle invasive disease (26, 27).

Increased MMP9 levels may be mediated by polymorphisms in the promoter region of the gene. A variety of transcription factor binding sites are in the MMP9 promoter region, including activator protein-1, nuclear factor-{kappa}b, and specificity protein-1 (28–30). In addition, the CA microsatellite and –1562 polymorphisms examined in this study are thought to play a role in MMP9 transcription. Greater numbers of CA repeats have been associated with greater expression of MMP9, such that 24 repeats yield ~20 times the production of MMP9 compared with <20 repeats (29, 31, 32).

The MMP9 microsatellite polymorphism has been associated with a higher risk of a number of conditions, including atherosclerosis, multiple sclerosis, mesangial sclerosis, aneurismal disease, and age-related macular degeneration, to name a few (24, 29, 33, 34). Despite the association of MMP9 with malignancy and invasiveness, to date, there is only one study reporting the association of the MMP9 microsatellite polymorphism with malignancy (35). There are, however, data suggesting that chemotherapy induces a shortening of the CA repeats (from 24 to 18), and that this is associated with the decreased expression of MMP9 in a lung cancer cell line (36). Interestingly, our findings showed that patients with a single, higher-expressing ≥24 CA repeat allele had a greater risk of invasive as opposed to superficial bladder cancer. Our results also suggest that smoking in combination with the greater expressing ≥24 CA repeat allele may increase the risk of bladder cancer invasiveness. We observed joint effects of certain MMP polymorphisms (MMP9 microsatellite and MMP12 –82) and smoking, supporting the hypothesis that those with tobacco exposure and variant MMP genotypes would be at an even greater risk of invasive disease. MMP9 expression is heightened by smoking exposure potentially by a nuclear factor-{kappa}b–mediated mechanism (37, 38). Although this study describes associations, it is possible that the variant MMP9 genotype and the adverse environmental exposure may interact resulting in a more invasive phenotype.

MMP12, which is also known as macrophage metalloelastase, is found on chromosome 11q22.3, along with MMP1, MMP3, and MMP8 (20). It is believed to be angiostatic (39). The –82 A/G polymorphism is located in the activator protein-1 transcription factor binding site, and the G allele is associated with decreased expression in vitro (40). Our data suggest that the lower-expressing GG genotype was associated with increased bladder cancer invasiveness, an effect that was heightened when combined with smoking exposure. A potential explanation is that loss of the angiostatic effects of MMP12 preferentially promotes the development of muscle-invasive disease.

We observed that several MMP SNPs may be associated with a protection from bladder cancer invasiveness in former smokers. As the effect of individual MMP polymorphisms on bladder cancer risk may be subtle, we compared the effect of a combination of polymorphisms and showed a significantly greater association (Supplementary Table S3). Many of the alleles that had a protective effect in former smokers are associated with increased expression of the protein, and it is known that the increased expression of tissue inhibitors of metalloproteinases is associated with higher stage and grade tumors (41, 42). There may be a complex balance between MMPs and their inhibitors. The absence of the protective association in current smokers may be an indication that heavy exposure to smoke overwhelms the genetic effects. Due to the small sample size of this analysis, these results should be interpreted with caution, as chance findings cannot be ruled out.

This study suggests that MMP polymorphisms modify the risk of invasive as opposed to superficial bladder cancer. Despite the large number of SNPs investigated and the great number of MMP genes analyzed, however, this represents only a fraction of a family of enzymes numbering >24. Although we analyzed those MMP genes that are believed to play an important role in the biology of bladder cancer, we cannot rule out the possibility that other polymorphisms in potentially more important members of this family may exist. Furthermore, it is always possible that the associations seen in this type of study are merely linked to the causative factors responsible for the changes in disease risk. Additional studies are therefore required to validate these findings and to further elucidate the functional effect of these polymorphisms on the biology of this disease.

In summary, genetic variations in the MMP family may contribute to the development of invasive bladder cancer. These results, once validated, may help to identify high-risk populations as well as determine an individual's risk of invasive bladder cancer. Further study of the biological ramifications of these polymorphisms may add to our understanding of the biology of the disease and provide potential foci for targeted therapies.


   Footnotes
 
Grant support: National Cancer Institute grants CA74880 and CA91846.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

A.K. Kader and J. Liu are considered equal contributors to this article.

Received 5/16/06; revised 1/15/07; accepted 2/ 7/07.


   References
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