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Invasiveness of Cutaneous Malignant Melanoma Is Influenced by Matrix Metalloproteinase 1 Gene Polymorphism¹

Human Genetics Research Division [S. Y., S. D., S. J. T., I. D., W. M. H.] and Medical Statistics Group [R. M. P.], University of Southampton School of Medicine, and Department of Histopathology, Southampton University Hospitals NHS Trust [A. C. B., J. M. T.], Southampton, United Kingdom

	ABSTRACT

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The matrix metalloproteinases (MMPs) are implicated in connective tissue destruction during cancer invasion and metastasis. A naturally occurring variant arising from the insertion or deletion of a guanine in the promoter of the MMP-1 gene has recently been reported and shown to influence its transcriptional activity in melanoma cells. In this study, MMP-1 genotype was determined in 139 Caucasian patients with cutaneous malignant melanoma. The insertion allele was associated with deep invasive, and therefore poorer-prognosis, primary tumors [(34% of patients with vertical growth phase tumor were homozygous for the insertion allele compared with 17% of patients with horizontal growth phase tumor (P = 0.0333; odds ratio = 2.51)]. These data suggest that the invasiveness of cutaneous malignant melanoma is influenced by variation in the MMP-1 gene promoter that affects MMP-1 expression.

	Introduction

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Degradation of the extracellular matrix and basement membrane barriers is a key process in tumor invasion and metastasis. There is strong evidence indicating that the MMPs,³ which possess proteolytic activities against extracellular matrix and basement membrane proteins, play an important role in this process and therefore facilitate tumor invasion and spread (1 , 2) . Recently, a naturally occurring sequence variation in the human MMP-1 gene promoter was reported (3) . This genetic variation arises from insertion or deletion of a G at position -1607 relative to the transcriptional start site; consequently one allele (insertion) has two 2Gs, whereas the other allele (deletion) has only 1G at this position. The insertion creates the core sequence (5'-GGA-3') of a binding site for the Ets transcription factors, and it was demonstrated in vitro that the 2G allele had a higher transcriptional activity in melanoma cells (3) . CMM is the most serious cutaneous malignancy. Relatively little is known of the genetic factors underlying susceptibility to and prognosis in sporadic CMM, although polymorphisms in several genes have been implicated (4, 5, 6) . In this study, we sought to determine whether this MMP-1 genetic polymorphism is associated with susceptibility to CMM in British Caucasian subjects, and whether this polymorphism influences CMM prognosis, i.e., is associated with known prognostic features of CMM, particularly those associated with tumor invasiveness, growth, recurrence, or metastasis.

	Subjects and Methods

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Subjects
Patients.
Formalin-fixed and paraffin-embedded tissue blocks from 139 CMM patients (presenting in 1986–1993) were retrieved from the files of the Histopathology Department, Southampton General Hospital (Southampton, United Kingdom). All specimens were re-reviewed by two histopathologists (A. C. B. and J. M. T.) and the original diagnoses of CMM confirmed.

Tumor Histopathology Data.
Histopathological prognostic features of each case were assessed as defined in the literature and used in previous studies (7 , 8) . Radial growth phase CMMs were defined as those limited in extent to the epidermis (melanoma in situ) or showing early invasion of the upper dermis but with dermal nests of melanocytes no larger than those at the dermoepidermal junction and containing no mitotic figures. Vertical growth phase CMM showed expansive growth within the dermis, evidenced by nests of neoplastic melanocytes that were larger than those at the dermoepidermal junction or by the presence of mitotic figures within dermally located melanocytes (8) . For vertical growth phase CMM, the mitotic count/mm² of tumor was assessed as nil, 1–6, or >6, and the number of tumor-infiltrating lymphocytes was evaluated as absent, nonbrisk/focal, or brisk (8) . The presence of tumor regression, defined as segmental tumor loss, was also recorded.

Clinical Follow-up Data.
The following variables were recorded for each patient, subject to availability of clinical data: (a) gender; (b) age; (c) site of CMM; (d) length of clinical follow-up; (e) presence of recurrent or metastatic tumor; (f) disease-free survival; and (g) overall survival time. The clinicopathological stage of each patient at initial presentation for whom full data were available was calculated using the Tumor-Node-Metastasis system (9) .

Controls.
Controls consisted of stored DNA samples derived from 142 cadaveric and noncadaveric solid organ and bone marrow donors. All patients and donors were Caucasian.

Preparation of DNA Samples
DNA was extracted from Formalin-fixed, paraffin wax-embedded tissue blocks from CMM patients as described previously (7 , 10) . Briefly, two to five 20-µm sections were cut from each tissue block and dewaxed in xylene (Merck, Ltd., Poole, United Kingdom) and xylene-ethanol washes. DNA was extracted from the resulting cellular material by proteinase-K digestion. Control DNA samples were originally prepared from peripheral blood by standard salt-precipitation protocols (11) .

Determination of Genotypes
A recently published method was used to determine the genotypes of the subjects (12) . Briefly, PCR was carried out in a total volume of 25 µl containing 50 ng of genomic DNA; 10 pmol of the forward and reverse primers (5'-TCGTGAGAATGTCTTCCCATT-3' and 5'-TCTTGGATTGATTTGAG- ATAAGTGAAATC-3', respectively); 200 mM each dATP, dCTP, dGTP and dTTP; 20 mM Tris-HCl (pH 8.4); 50 mM KCl; 0.05% (v/v) W1 (Life Technologies, Inc.); 1.5 mM MgCl₂; and 1 unit Taq polymerase (Life Technologies, Inc.). The solution was overlaid with 25 µl of liquid paraffin and incubated for 1 min at 95°C, and then by 35 cycles of 30 s at 95°C, 30 s at 55°C, and 30 s at 72°C. A 15-µl aliquot of PCR products was mixed with a 5-µl solution containing 2 µl of 10x NEBuffer 2 [50 mM NaCl, 10 mM Tris-HCl, 10 mM MgCl₂, and 1 mM DTT (pH 7.9)], 0.2 µl of BSA (10 mg/ml), 0.3 µl Xmn I (20 units/ml), and 2.5 µl of sterile deionized H₂O. The 5-µl aliquot of the digests was mixed with 2 µl of loading buffer and electrophoresed on a 10% horizontal nondenaturing polyacrylamide gel at 150 V for 2.5 h. The gel was then stained with Vistra Green (Amersham) and scanned with a fluorimager (FI595; Molecular Dynamics, Sunnyvale, CA).

Statistical Analyses
Differences in genotype and allele frequencies between the patients and the healthy British Caucasian controls were tested using ² analyses. Genotype and allele frequencies were compared similarly between British Caucasian and Japanese healthy subjects (latter frequencies derived from the literature (13) . Odds ratios and asymptotic confidence intervals were calculated. Genotype frequencies were also compared within patient subgroups according to tumor growth phase, Breslow depth (invasive CMM), mitotic index (vertical growth phase CMM), clinicopathological phase at presentation, and the presence of disease recurrence/metastasis. Disease-free survival according to genotype was displayed graphically among surgically treated subjects using Kaplan-Meier curves. Relative hazards between genotypes and their associated 95% confidence intervals were estimated within a Cox regression model, and differences between genotypes were tested from the log likelihood ratio. Survival analysis was carried out within Stata.

	Results

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MMP-1 Genotype and Susceptibility of Melanoma.
MMP-1 genotype according to insertion (2G allele) or deletion (1G allele) of a G at position -1607 (3) was determined in 139 patients and 142 healthy Caucasian subjects. No statistically significant difference in genotype and allele frequencies was detected between the melanoma patients and the healthy subjects, with the frequency of the 2G allele being 53% in patients and 47% in healthy subjects (Table 1) . The genotype frequencies in both samples were consistent with Hardy-Weinberg equilibrium distribution.

MMP-1 Genotype and Invasiveness of Melanoma.
In the CMM patients, there was an association between the 2G allele and deep invasive tumors; 34% of patients with vertical growth phase lesions were homozygous for the 2G allele compared with 17% of patients with horizontal growth phase lesions (P = 0.0333; Table 2 ).

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. Disease-free survival in CMM series according to MMP-1 genotype. Analysis of disease-free survival was carried out in subjects who had a complete recovery from surgery and were then followed up clinically. There was a trend toward decreased disease-free survival in patients carrying the 2G allele.

	Discussion

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CMM is a serious and potentially fatal condition, with the most important environmental risk factor being UV light exposure and 5–10% of all cases being familial (14) . In nonfamilial CMM cases, both susceptibility to and prognosis in this malignancy have been shown to be influenced by human leukocyte antigen DQB1 polymorphisms (7) or DQB1-associated haplotypes (15) , although other nonimmunogenetic factors have also been implicated (4, 5, 6) . The most important prognostic factor is stage at time of presentation, and a melanoma is most capable of being cured by surgical excision when it is at the superficial stage ("radial" growth phase CMM, as opposed to vertical growth phase CMM; Ref. 16 ). Radial growth phase CMMs exist solely within the epidermis or may contain small numbers of nondividing cells within the superficial dermis. Vertical growth phase CMMs contain neoplastic melanocytes actively growing within the dermis and possess the capability to metastasize to regional lymph nodes and distant organs. In vertical growth phase CMMs, prognosis is also influenced by the depth of invasion of the lesion (Breslow depth and Clarke’s level), the mitotic index and presence of tumor-infiltrating lymphocytes within the dermal component, and the presence or absence of tumor regression (8) .

Several MMPs, including MMP-1, are expressed in cutaneous melanomas, and it has been demonstrated that these MMPs play a role in melanoma cell invasion with overexpression being associated with metastasis and unfavorable prognosis (17, 18, 19) . As mentioned above, the MMP-1 gene variation investigated in this study has been shown previously to have an allele-specific effect on the levels of MMP expression in cultured melanoma cells (3) . It has also been reported that ovarian tumor and endometrial cancer tissues from patients carrying the 2G allele contain higher levels of MMP-1 transcripts compared with those from patients not carrying this allele (13 , 20) . In a recent Japanese study of ovarian cancer, the proportion of patients who carried the 2G allele was significantly higher than in the control subjects, suggesting that individuals carrying the 2G allele are genetically predisposed to the development of ovarian cancer (13) . In our study, no difference in MMP-1 genotype frequency between CMM patients and healthy subjects was detected. This may indicate a difference in genetic risk factors between melanoma and ovarian cancer or a difference in genetic risk factors for cancers between Orientals and Caucasians. It was noted that the MMP-1 genotype frequencies within our healthy Caucasian control population differed significantly from those within the healthy Japanese subjects used in a previous study (13) .

The association of the 2G allele of the MMP-1 gene with vertical growth phase CMM and the trend toward lower survival rate observed in this study is consistent with the hypothesis that variation in MMP genes can influence the potential for tumor invasion and metastasis through modulation of the expression and/or activity of these extracellular matrix-degrading enzymes. No associations were demonstrable between MMP-1 genotype and the histopathological markers of prognosis in vertical growth phase CMM that we examined. Histological features such as Breslow depth, mitotic index, and the presence of tumor-infiltrating lymphocytes have been proven to correlate with prognosis in vertical growth phase CMM (8) . Therefore, examination of a larger patient series may be required to investigate potential associations between MMP-1 genotype and both these more detailed histological features and clinical outcome.

To our knowledge, this is the first report of a study of a naturally occurring variant in an MMP gene in relation to the invasiveness of carcinoma. The data generated in this study support the hypothesis that variation in the MMP-1 gene influences the potential for invasion and metastasis of CMM through modulation of the expression of this matrix-degrading enzyme.

	FOOTNOTES

 
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.

¹ S. Y. thanks the British Heart Foundation for support on studies of MMP genes (PG/98183 and PG/98192). This work was also supported by a research grant to W. M. H., A. C. B., and J. M. T. from the Association for International Cancer Research, St. Andrews, Scotland (99-121). I. D. is a Lister Institute Research Professor and thanks the United Kingdom MRC (Program Grant G9828424) and the Wessex Medical Trust for support for facilities.

² To whom requests for reprints should be addressed, at Human Genetics, Duthie Building (Mailpoint 808), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, United Kingdom. Phone: 44 (0) 23-8079-4929; Fax: 44 (0) 23-8079-4264; E-mail: Shu.Ye{at}soton.ac.uk

³ The abbreviations used are: MMP, matrix metalloproteinase; G, guanine; CMM, cutaneous malignant melanoma.

Received 8/17/00. Accepted 12/20/00.

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ye, S. Articles by Howell, W. M. Search for Related Content PubMed PubMed Citation Articles by Ye, S. Articles by Howell, W. M.