The collagenase-1 (MMP-1) gene promoter polymorphism - 1607/2G is associated with favourable prognosis in patients with colorectal cancer

Abstract

Matrix metalloproteinase (MMP) overexpression has been implicated in the pathogenesis of colorectal carcinoma (CRC). Accumulating evidence suggests that MMP promoter single nucleotide polymorphisms (SNPs) effecting gene transcription are associated with enhanced susceptibility for the development of malignant disease, increased tumour invasiveness and poor patient survival. The aim of the current investigation was to determine whether such associations exist in a large CRC patient/control study population. Using an allelic discrimination real-time polymerase chain reaction, polymorphisms in the MMP-1, MMP-2 and MMP-3 gene promoters (À1607, À1306, and À1612 bp, respectively) were assessed in normal blood mononuclear cells from patients with CRC (n ¼ 503) and control subjects (n ¼ 471). Genotypes corresponding to each MMP SNP were correlated with tumour characteristics and clinical outcome. The frequency of each genotype was not statistically different between patients and control subjects and no significant differences were noted between the genotypes and tumour characteristics for the three MMP SNPs. CRC patients with the 2G/2G genotype for the MMP-1 SNP had significantly better 5-year survival compared to patients with a 1G allele (Po0.05). Our results demonstrate that CRC patients with a 2G/2G genotype in the MMP-1 gene promoter SNP have a favourable prognosis. Although our results were unexpected, given that this genotype is associated with enhanced MMP-1 transcriptional activity, they are consistent with recent data highlighting the anti-tumorigenic properties of MMPs.

Single-nucleotide polymorphisms of matrix metalloproteinases and their inhibitors in gastrointestinal cancer

“…These findings were not supported by Hettiaratchi et al [96] , Elander et al [90] and Ohtani et al [103] , who found no influence of the MMP-2 genotype on the colorectal cancer risk (Figure 2). Difference in ethnicity (Australian vs European vs Japanese) or sample size might be the underlying cause of this discrepancy.…”

“…Two meta analyses, both including the study of Xu et al, showed no association between the MMP2 1306 C/T poly morphism and colorectal cancer susceptibility [87,100] . Xu et al [104] also reported that patients with the CC genotype had more frequent serosa/adventitia involvement, while none of the other studies described any correlation with clinicopathological parameters or survival, except for the study of Langers et al, where the TT genotype was shown to be an indicator of poor 10year survival [8993,96,97,99,103,105] . In the Xu et al [104] cohort of 126 CRC patients and 126 control patients, two other polymorphisms of MMP2 (790 T/G, 955 A/C) were not associated with cancer susceptibility or infiltration depth, while GG genotype carriers of the MMP2 1575 G/A polymorphism had an increased risk of developing CRC and more frequent serosa or adventitia invasion compared to the other geno types, similar to that with the 1306 CC genotype [102] .…”

“…In two metaanalyses, 2Gallele carriers showed a significantly increased risk of developing colorectal cancer when com pared with homozygous 1G allele carriers [87,100] . However, the large cohort of Hettiaratchi et al [96] was not included in these metaanalyses and inclusion of this study might lead to loss of significance.…”

“…With exception of the studies of Fang et al and Hettiaratchi et al, all studies included a relatively small number of patients, which could explain the differences in results. Hettiaratchi et al included the largest cohort (503 Australian CRC patients, 471 controls) of all studies so far [96] . Besides the lack of association be tween the genotype and CRC susceptibility, in this cohort the 5year survival was increased in 2G/2G homozygotes.…”

Matrix Metalloproteinase Single-Nucleotide Polymorphisms and Haplotypes Predict Breast Cancer Progression

“…In our study, when the Caucasian patients were subtracted from the ethnically mixed group, and the latter analyzed, there was no association between the T allele and node status when corrected for grade (P = 0.96; odds ratio, 1.05; 95% CI, 0.18-5.93). Similarly, in colorectal cancer, whereas a relationship between the MMP-1 2G/2G genotype and poor prognosis has been identified in an Italian cohort of patients with colorectal cancer (30), no such relationship was identified in a recent large Australian study (31).…”