A functional polymorphism in the matrix metalloproteinase‐1 gene promoter is associated with susceptibility and aggressiveness of head and neck cancer

Abstract

Matrix metalloproteinases (MMPs) play an important role in several steps of cancer development. A single guanine insertion polymorphism (2G) in the MMP1 promoter sequence at 21,607 creates an Ets binding site and thus results in enhancing transcriptional activity. This study aimed to evaluate the contribution of this 2G polymorphism on susceptibility and aggressiveness of HNSCC. A panel of HNSCC cell lines and peritumoral fibroblasts were examined for the MMP1 genotypes and expression levels. Genomic DNA was extracted from peripheral blood of 300 patients with newly diagnosed HNSCC and from 300 age-and gender-matched cancer-free controls. Genotyping was carried out using a PCR-RFLP assay. The levels of MMP1 mRNA expression were evaluated by the quantitative RT-PCR and a correlation with different genotype was determined. Odds ratio (OR) for cancer risk were calculated using multivariate logistic regression. In addition, a correlation between the 2G/2G genotype and clinicopathological parameters was examined. Eleven out of 18 HNSCC cell lines showed the 2G/2G genotype (61%) and only 1 cell line had the 1G/1G genotype (5.6%). Cell lines with the 2G/2G genotype expressed significantly higher mean MMP1 mRNA level than those with other genotypes. In clinical model, subjects carrying the homozygous 2G/2G genotype had a higher risk of head and neck cancer compared with subjects with other genotypes (adjusted OR: 2.28; 95% CI: 1.58-3.27), controlling for major confounders. A correlation between promoter polymorphisms and the levels of MMP1 expression in cancer tissues was found, and this 2G/2G genotype was correlated with the adverse clinicopathological parameters. Finally, the highest level of MMP1 enhancement was demonstrated in the coculture of tumor cells and peritumoral fibroblasts of 2G homozygotes. These findings suggest that the presence of 2G polymorphism at the MMP1 promoter is associated with the development and progression of HNSCC. ' 2005 Wiley-Liss, Inc.Key words: head and neck cancer; squamous cell carcinoma; matrix metalloproteinase; single nucleotide polymorphism Head and neck squamous cell carcinoma (HNSCC) is 1 of the 5 most common cancers worldwide. 1 In Thailand, HNSCC accounts for 1 in 4 cancers in men and is the fourth most common cancer in women. 2 Although smoking and alcohol use play a major role in the etiology of these malignancies, only a fraction of smokers and drinkers develop this disease, suggesting a genetic susceptibility in the general population. In addition, the inherited genetic factors in some HNSCC patients may be responsible for a more aggressive disease. The ability to identify such high-risk individuals will have major influence in the cancer prevention and treatment programs in the future.The matrix metalloproteinases (MMPs), a family of 23 extracellular endopeptidases with enzymatic activity against almost all protein components of the extracellular matrix (ECM), have been implicated in the invasion and metastasis of HNSCC. 3 Recent work has suggested that, in addition to pr...

Association between Polymorphisms in the Promoter Regions of Matrix Metalloproteinases (MMPs) and Risk of Cancer Metastasis: A Meta-Analysis

“…Different genotyping methods were used in these studies, including the classical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 21 of 33 studies [17]–[21], [23], [25]–[30], [39], [41]–[48], PCR-allele specific refractory mutation system analysis (ARMS) in 2 studies [7], [40], TaqMan assay in 4 studies [19], [22], [34], [37], PCR-sequencing in 6 studies [24], [31], [33], [35]–[36], [38], and PCR – fluorescent fragment analysis in 2 studies [28], [32].…”

“…The significance of pooled ORs under the recessive model was also not influenced by omitting those four studies. In the present study, most genotype data were based on the time of diagnosis except for the studies [21]–[22] on the time of follow-up. Therefore, sensitivity analysis was performed by omitting the two studies.…”

Single nucleotide polymorphisms in matrix metalloproteinase genes and lung cancer chemotherapy response and prognosis

“…The promoter polymorphism is responsible for lowering the transcription by disruption of an AP1-binding site [15], whereas the polymorphism A1082G has not been shown to have a phenotypic effect. The GG allele of the functional MMP1 G-1607GG polymorphism is associated with higher expression levels of MMP1 and with increased susceptibility to head and neck and lung cancer [16,17].…”

Frequent Deletion of BRG1 Locus at 19p13 Predicts Recurrence and Previous Cancer History in Oral Squamous Cell Carcinomas

“…Several chromosomal loci are deleted early during carcinogenic process. Le et al 16) reported that a stepwise allelic loss occurred involving 9p21, 3p, p53, RB1 or p16 and/or inherited genetic predisposition 25) or polymorphic alterations related with the activity of genes 26,27) could be responsible for aggressive tumor phenotype or secondary cancer development in younger patients. Those patients are likely to be cancer prone due to alterations of the TSGs or genetic predisposition for a long time.…”