Prognostic Significance of MMP-1 and MMP-3 Functional Promoter Polymorphisms in Colorectal Cancer

594 Vol. 11, 594–599, January 15, 2005 Clinical Cancer Research

Franck Zinzindohoue´,1 Thierry Lecomte,2 INTRODUCTION Jean-Marc Ferraz,2 Anne-Marie Houllier,1 Matrix metalloproteinase (MMP) belongs to a large group Paul-Henri Cugnenc,2 Anne Berger,2 of proteases, which includes over 22 known human zinc- He´le`ne Blons,1 and Pierre Laurent-Puig1 dependent proteolytic enzymes. These are capable of breaking essentially all components of the extracellular matrix (1, 2). 1INSERM U490 Laboratoire de toxicologie Molećulaire and 2 MMPs take part in high tissue turnover and remodeling, both Poˆle de cance´rologie Hoˆpital europeén Georges Pompidou, Paris, France physiologic and pathologic conditions such as cancer. MMPs are also implicated in all steps of tumorogenesis, cancer invasion, and metastasis (3). Tumor invasion and metastasis formation ABSTRACT always begin with blood and lymphatic vessel infiltration. As Purpose: Matrix metalloproteinase (MMP) belongs to a these processes involve proteolysis of the extracellular matrix, large group of proteases capable of breaking essentially all MMPs are suggested to play a major role in tumor progression. components of the extracellular matrix. They are implicated Colorectal cancer is the most common malignancy of the in all steps of tumorogenesis, cancer invasion, and gastrointestinal tract. It is the third cause of cancer overall and metastasis. Among them, metalloproteinase type 1 (MMP- the second leading cause of cancer-related death in the Europe 1) is implicated in tumor invasion and metastasis in and the United States with an incidence of 300,000 new cases different types of cancers including colorectal cancer in (4). It still carries a relatively poor prognosis despite recent improvements in early diagnosis, surgical techniques, and which its expression was correlated with poor prognosis. A chemotherapy. About 40% of the patients who undergo operative polymorphism in the promoter region of the MMP-1 gene resections will die within 5 years due to recurrent disease or leads to a variation of its level of transcription. metastases. MMPs are essential for tumor cells to penetrate the Study Design: MMP-1 -1607ins/delG and MMP-3 - 1612 basement membrane and colonize distant sites. Their role was ins/delA promoter polymorphisms were genotyped by shown in colorectal cancer (5, 6). Among MMPs, MMP-1 is the multiplex PCR from 201 colorectal cancer patients. The most ubiquitously expressed interstitial collagenase. Overex- median follow-up of patients was 30 months. The MMP pression of MMP-1 was implicated in tumor invasion and genotypes were correlated to clinical outcome. metastasis in different types of cancers including colorectal Results: Patients with the -1607insG/-1607insG MMP-1 cancer (7) and its expression in colorectal cancer tumor cells was genotype had significantly worse specific survival than the correlated with poor prognosis (8). Rutter et al. (9) reported in others in the whole series (P < 0.04), in stage I to III patients melanoma a functional single nucleotide polymorphism 1607del/ (P < 0.001), and in patients stage I and II (P < 0.01). In insG) in the MMP-1 promoter with a guanine (G) insertion. It creates an Ets binding site, 5-GGA-3, which increases the multivariate analysis, MMP-1-1607insG allele showed to be promoter activity. Thus, the MMP-1-1607insG allele has an independent poor prognostic factor after adjustment on significantly higher transcriptional activity than the MMP- stage, age, and the use of adjuvant chemotherapy. MMP-3 1-1607delG allele. An association between the presence of polymorphism was not associated with survival. MMP-1-1607insG allele in the MMP-1 promoter and cancer Conclusions: In the subgroups of nondistant meta- susceptibility was described in ovarian (10) endometrial (11), tastic patients (stages I and II, and stages I-III), an and lung (12) cancers. Furthermore in melanoma (13), cervical inverse relation between the number of MMP-1-1607insG cancer (14), and colorectal cancer (15), the presence of MMP1- allele and survival was observed suggesting a gene dosage 1607insG allele was significantly associated with stage or effect. Our results are consistent with the importance of invasiveness of the tumor. MMP-1-1607ins/delG functional polymorphism in regulat- MMP-3 is another important MMP interacting with tumor ing transcription level and with the relationship between microenvironment. Its activities are complementary to MMP-1. MMP-1 expression and cancer invasion, metastasis, and It is located on the cluster gene 11q22, close to MMP-1 gene. A prognosis. MMP-3-1612del/insA polymorphism in the promoter of the MMP-3 gene was described (16). In vitro analysis showed that the MMP-3-1612insA allele is associated with low transcription levels (17). In a case-control study, the frequency of the MMP- 3-1612delA allele was higher in the breast cancer group than in Received 7/3/04; revised 9/12/04; accepted 10/5/04. controls and was more prevalent in the metastatic group than The costs of publication of this article were defrayed in part by the in the nonmetastatic one (18) suggesting a link between the payment of page charges. This article must therefore be hereby marked presence of the MMP-3-1612delA allele with breast cancer advertisement in accordance with 18 U.S.C. Section 1734 solely to susceptibility and prognosis. In colorectal cancer case-control indicate this fact. studies, discrepant results were observed concerning the Requests for reprints: Pierre Laurent-Puig, U490 Laboratoire de association between MMP-3 polymorphism and cancer risk (19). Toxicologie Molećulaire, 45 rue des Saints Pe`res 75006, Paris, France. Phone: 331-428-62081; Fax: 331-428-62072; E-mail: pierre.laurent-puig@ It is noteworthy that the haplotypes MMP-1-1607insG/ biomedicale.univ-paris5.fr. MMP-3-1612insA and MMP-1-1607delG /MMP-3-1612delA D2005 American Association for Cancer Research. are more frequently found than expected (20, 21) leading to a

preferred association of the higher and the lower transcriptional genetic polymorphisms analyzed among groups of patients activity alleles for MMP-1 and MMP-3 genes, respectively. according to tumor stage and tumor location and in the To evaluate the role of the single nucleotide promoter relationship between each categorical variable with MMP-1 functional polymorphisms of MMP-1 and MMP-3 genes on patient and MMP-3 promoter polymorphisms. survival in colorectal cancer, we genotyped them in 201 colorectal Deviation from Hardy-Weinberg equilibrium was tested cancer patients. We found that MMP-1-1607insG allele was using v2 test with 1 df. associated with a worse prognosis independently from tumor stage. Survival and End Points The patients were followed every 3 months by clinical MATERIALS AND METHODS examination during the first three postoperative years and then Between April 1995 and May 2002, among the consecutive every 6 months. An abdominal ultrasonography and a chest X-ray patients with colorectal cancer referred to the department of were done every 3 and 6 months, respectively, in nonmetastatic General and Oncological surgery of Georges Pompidou Hospital patients. Survival and progression end points were determined by (tertiary care hospital), 357 newly diagnosed patients, without reviewing medical records and interviewing patient’s general preoperative radiotherapy or previous cancer history were physician or patient’s family. None of the patients were lost of eligible. Among them, an informed consent was obtained from follow-up. All clinical data were reviewed by three of the authors the 201 patients enrolled in this study. There were 96 males and (T.L., A.B., and F.Z.) without knowledge of molecular data. 105 females, sex ratio was 1.1, and mean age 69 F 11 years Survival was calculated as the time from surgery to death (range, 35-95 years). The median follow-up was 30 months from any cause for overall survival, to death from cancer for (range, 3-87 months). Tumor locations were proximal in 63 cases cancer-specific survival, to recurrence for disease-free survival, or (cephalad to the splenic flexure), distal colon in 98 cases, and to the date of last follow-up. For overall survival, all deaths, rectal in 40 cases. According to the tumor-node-metastasis irrespective of cause, were considered events. For cancer-specific classification, 22, 63, 52, and 64 patients were, respectively, survival, only cancer-related deaths were considered; data classified stage I, stage II, stage III, and stage IV. Chemotherapy concerning the patients who died from other causes or who were regimens based on 5-fluorouracil were administrated in 48 patients still alive at the end of our study were censored. Survival curves in stages III and IV, depending on age and physical conditions. were constructed using the Kaplan-Meier method and compared Seventy other patients received palliative chemotherapy for using the log-rank test. recurrence. Samples from tumor and nontumor colorectal tissues Multivariate analyses were done by Cox proportional were harvested during surgery. Normal tissues were collected at hazards model. The tumor tumor-node-metastasis, age and least 5 cm distant from tumor. Samples were stored at À80jC until tumor location, and MMP-1 and MMP-3 promoter polymor- DNA extraction was done using the Qiamp tissue extraction kit phisms were included in the multivariate Cox regressions. (Qiagen, Courtaboeuf, France).

MMP-1 and MMP-3 Genotyping RESULTS Multiplex PCR was done on non tumor tissues allowing Among the 201 patients included in this series, DNA coamplification of MMP-1 and MMP-3 fragments extraction failed in 13 patients, and genotyping could not be using the following primers: 5V6FAM-CCCTCTTGAACTCA- achieved in 7 and 10 patients for MMP-1 and MMP-3 CATGTTATG-3Vand 5V-ACTTTCCTCCCCTTATGGATTCC-3V polymorphism, respectively. Histologic and clinical data from for MMP-1 and 5-TCCTCATATCAATGTGGCCAAA- 3V and thepatientsaregivenaccordingtoMMP-1 and MMP-3 5V6FAM-CGGCACCTGGCCTAAAGAC-3V for MMP-3 as pre- genotype in Table 1. There were no significant differences in viously described (22). Briefly, 40 ng of genomic DNA were the frequency of MMP-1 and MMP-3 genotypes according to amplified by 0.5 units of HotStar Taq polymerase (Qiagen, Les gender, age, tumor location, and stage (Table 1). Ulis, France), 200 nmol/L deoxynucleoside triphosphates, 2 mmol/L MgCl2, and 300 nmol/L of each primer on a GeneAmp MMP-1 and MMP-3 Genotypes PCR system 9700 (Applied Biosystems, Courtaboeuf, France). MMP-1-1607delG and MMP-1-1607insG allele frequen- Fragments were separated after dilution on an ABI 310 genetic cies were 0.48 and 0.52, respectively, and for MMP-3-1612delA analyzer (Applied Biosystems). and MMP-3-1612insA allele frequencies were 0.44 and 0.56, To rule out classification errors from our MMP-1 and MMP-3 respectively. Genotype distribution of MMP-3 was consistent genotyping methods, first we genotyped MMP-1 on a subset of with Hardy-Weinberg equilibrium, whereas genotype distribu- 20 controls with another published method (12). We reproduce tion of MMP-1 was not (P < 0.002). The number of MMP-1 individually the same genotyping results. Second, we validated heterozygous patients was less than expected. Thereby, we were our MMP-3 genotyping method by characterizing the 23 CEPH not able to calculate the linkage disequilibrium between MMP-1 individuals, for whom MMP-3 genotype is available in the and MMP-3 polymorphisms that was observed in previous National Center for Biotechnology Information single nucleotide published studies (21, 22). polymorphism database. We found identical genotyping data. Survival Analysis Statistical Analysis In a first attempt, we considered the whole series Statistical tests were done with STATA software (STATA including patients with metastasis (n = 190). The median 7.0; College Station, TX). The v2 or Fisher’s two-tailed exact survival for homozygous MMP-1-1607delG patients was not tests were used to determine differences in the repartition of the reached, the median survivals were 76 months and 42 months

Table 1 Genotype frequencies of MMP-1 and MMP-3 according to gender, age, tumor location, and stage MMP-1-1607 MMP-3-1612 delG/delG, delG/insG, insG/insG, ND P delA/delA, delA/insA, insA/insA, ND P n (%) n (%) n (%) n (%) n (%) n (%) Gender M 19 (20) 36 (40) 35 (40) 6 0.08 24 (25.5) 42 (44.6) 28 (29.9) 11 0.33 F 35 (35) 37 (37) 28 (28) 5 16 (18.2) 38 (43.2) 34 (38.6) 8 Location Right 14 (24.5) 20 (35) 23 (40.5) 6 0.50 14 (25) 23 (41) 19 (34) 7 0.66 Left 26 (28) 40 (42) 27 (28) 5 19 (21) 38 (41.7) 34 (37.3) 7 Rectum 14 (35) 13 (32.5) 13 (32.5) 0 7 (20) 19 (54.3) 9 (25.7) 5 Stage NS I 6 (30) 7 (35) 7 (35) 2 0.92 4 (21) 5 (26) 10 (53) 3 0.47 II 15 (24.5) 22 (36) 24 (39.5) 2 10 (18) 26 (47) 19 (35) 8 III 16 (31.5) 20 (39) 15 (29.5) 1 10 (21) 23 (48) 15 (31) 4 IV 17 (29) 24 (41) 17 (30) 6 16 (27) 26 (43) 18 (30) 4 Mean age 70 F 12 66 F 13 70 F 11 0.09 69 F 13 66 F 13 70 F 12 0.20 Abbreviation: ND, nondetermined.

for heterozygous and homozygous MMP-1-1607insG patients, of 201 colorectal cancer patients. The frequencies of the different respectively (Fig. 1A, P < 0.09 log-rank test). A significant MMP-1 and MMP-3 alleles were consistent with those observed difference for specific survival between MMP-1-1607delG by others in Caucasian populations (12, 19). However, the homozygous patients, heterozygous patients and MMP- 1-1607insG homozygous was observed (Fig. 1B, P < 0.05 log-rank test). In a second analysis, we excluded stage IV patients. In these remaining patients (n = 132), significant differences were observed between MMP-1-1607delG homozygous patients, heterozygous patients and MMP-1-1607insG homozygous patients for overall survival (P = 0.007 log-rank test; Fig. 2A) as well as for specific survival (P < 0.001, log-rank test; Fig. 2B) and for disease-free survival (P = 0.005, log-rank test; Fig. 2C). A multivariate analysis was done. We found that MMP-1 genotype was an independent prognostic factor of overall survival (Table 2) after adjustment on stage age and the use of adjuvant chemotherapy. In a third analysis, we only included patients with stage I and II tumors (n = 81) in which the use adjuvant chemotherapy is matter of debate. Significant differences were observed among MMP-1-1607delG homozygous patients, MMP-1-1607delG heterozygous patients, and MMP-1-1607insG homozygous patients in overall survival (P < 0.02, log-rank test; Fig. 3A) as well as for specific survival (P < 0.01, Fig. 3B) and for disease-free survival (P < 0.03, log-rank test; Fig. 3C). The MMP-1 genotype was found to be an independent prognostic factor of survival after adjustment on age, stage, and the use of chemotherapy. Because no death occurred during the observa- tions period time for MMP-1-1607delG homozygous patients taken as reference group, we were not able to calculate the odd ratio of the different genotypes. Similar analyses were done for MMP-3 genotypes. No significant differences were observed in overall, specific, or disease-free survival according to the different MMP-3 genotypes.

DISCUSSION We investigated the influence of MMP-1 and MMP-3 promoter polymorphisms known to modulate MMP-1 and Fig. 1 A, overall survival for MMP-1 genotypes; P < 0.09, log-rank MMP-3 expression level (23), as prognostic factors in a series test. B, specific survival for MMP-1 genotypes; P < 0.05, log-rank test.

distribution of MMP-1 genotypes in our series was not consistent cancer (21) or could indicate the existence of stratification with the Hardy-Weinberg equilibrium. This departure from the factors in our series of colorectal cancer patients. When we Hardy-Weinberg equilibrium either could be due to the studied the MMP-1 genotypes distribution according to tumor association of the MMP-1 gene polymorphism with colorectal stage, the distribution was consistent with the Hardy-Weinberg

Fig. 2 A, overall survival of nonmetastatic patients for MMP-1 Fig. 3 A, overall survival of stage I and stage II patients for MMP-1 genotypes; P = 0.007, log-rank test. B, specific survival of nonmetastatic genotypes; P < 0.02, log-rank test. B, specific survival of stage I and patients for MMP-1 genotypes; P < 0.001, log-rank test. C, disease-free stage II patients for MMP-1 genotypes; P < 0.01, log-rank test. C, survival of nonmetastatic patients for MMP-1 genotypes; P = 0.005, disease-free survival of stage I and stage II patients for MMP-1 log-rank test. genotypes; P < 0.03, log-rank test.

Table 2 Survival analyses according to MMP-1 and MMP-3 genotypes Crude 95% 95% Time hazard Confidence Adjusted Confidence Variable Categories n Events at risk ratio interval P hazard ratio interval P MMP-1 Overall survival -1607delG/-1607delG 37 5 1691 1 1 -1607delG/-1607insG 49 13 1840 2.45 0.87-6.89 0.088 3.8 1.3-11.0 0.014 -1607insG/-1607insG 46 20 1595 4.24 1.57-11.42 0.004 5.4 2-14.7 0.001 Cancer-specific survival -1607delG/-1607delG 37 3 1691 1 1 -1607delG/-1607insG 49 5 1840 1.6 0.38-6.73 0.51 2.09 0.48-9.02 0.32 -1607insG/-1607insG 46 16 1595 5.86 1.69-20.38 0.005 8.52 2.38-30.6 0.001 Disease-free survival -1607delG/-1607delG 37 5 1626 1 -1607delG/-1607insG 49 6 1713 1.09 0.33-3.59 0.88 1.25 0.37-4.22 0.71 -1607insG/-1607insG 46 16 1374 3.46 1.26-9.48 0.016 4.1 1.47-11.44 0.007 MMP-3 Overall survival -1612delA/-1612delA 24 4 1071 1 1 -1612delA/-1612insA 54 18 1993 2.32 0.77-6.9 0.13 2.33 0.78-6.96 0.12 -1612insA/-1612insA 44 12 1550 2.15 0.68-6.7 0.18 2.36 0.74-7.5 0.14 Cancer-specific survival -1612delA/-1612delA 24 3 1071 1 1 -1612delA/-1612insA 54 10 1993 1.67 0.45-6.18 0.44 1.8 0.48-6.7 0.37 -1612insA/-1612insA 44 8 1550 2 0.52-7.6 0.3 2.18 0.56-8.4 0.26 Disease-free survival -1612delA/-1612delA 24 5 1046 1 1 -1612delA/-1612insA 54 11 1735 1.2 0.41-3.47 0.73 1.24 0.42-3.6 0.68 -1612insA/-1612insA 44 8 1450 1 0.33-3.16 0.95 1.07 0.34-3.3 0.9 NOTE. n, no. patients; events, no. events. Adjusted hazard ratio on age, use of adjuvant chemotherapy, and stage.

equilibrium in stages III and IV, whereas it was not in stages I MMP-1 genotype was found to be an independent prognostic and II, suggesting an association of one allele with prognosis. factor of overall survival after adjustment on stage, age, and the The MMP-1-1607insG and MMP-3-1612insA alleles and the use of adjuvant chemotherapy (Table 2). MMP-1-1607delG and MMP-3-1612delA alleles where found in One of the most important issues of colon cancer patient a linkage disequilibrium in several studies, the DV coefficient management is the determination of prognostic factors in early varies from 0.50 to 0.92 according to the ethnic origin of the stages of the disease in order to determine which patients are at patients (21, 22). Our first intention was to investigate the MMP- risk of recurrence or poor prognosis and then would benefit from 1 and MMP-3 haplotypic effects on colorectal cancer patients. a chemotherapy regimen. When we focused on stages I and II, However, the absence of Hardy-Weinberg equilibrium for MMP- patients bearing the MMP-1-1607insG allele showed a 1 genotype distribution did not allow us to infer MMP-1 and poor evolution whereas no death was observed for the MMP- MMP-3 haplotype frequencies. Thus, we separately investigated 1-1607delG homozygous patients. the role of each genotype on patient survival. Concerning the different MMP-3 genotype patients groups, In 1996, Murray et al. (8) found that the MMP-1 protein we were unable to show any relation between the different expression in colorectal cancer cell was associated with a poor patient genotype groups and survival. In a previous study, we prognosis. This prognostic factor was independent of tumor- showed in head and neck cancer patients that MMP-3-1612insA node-metastasis classification. Moreover, in 2001 Ghilardi et al. homozygous patients had a better response to 5-fluorouracil (15) found that the MMP-1-1607insG promoter allele may favor cisplatin–based chemotherapy regimens (22). In the present the tumor growth and the metastatic spread in colorectal cancer series, our results seem to be independent to the administration patients and then could be a factor of worse prognosis. In our of 5-fluorouracil–based adjuvant chemotherapy as shown in study, considering the whole series, we found a significantly multivariate analyses. worse cancer-specific survival in the MMP-1-1607insG homo- Our results are consistent with the importance of MMP- zygous patients group as compared with both heterozygous and 1-1607ins/delG functional polymorphism in regulating tran- MMP-1-1607delG homozygous patients groups. When we scription level and with the relationship between MMP-1 excluded metastatic patients at the time of diagnosis, a expression and cancer invasion, metastasis and prognosis significant inverse relation was observed between the number described by others (13–15). Furthermore, it is interesting to of MMP-1-1607insG allele and survival among colorectal cancer underline that the genotype analysis was achieved in nontumor patients suggesting a gene dosage effect. This inverse relation tissues suggesting that this prognostic factor could be determine was observed for overall, specific, and disease-free survivals. before tumor staging, independently of the tumor characteristics These results were confirmed in a multivariate analysis in which themselves.

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Franck Zinzindohoué, Thierry Lecomte, Jean-Marc Ferraz, et al.

Clin Cancer Res 2005;11:594-599.

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