Association of MMP3 -1171(5A>6A) Polymorphism with Lung Cancer in Lebanon

Introduction

Lung cancer is the most commonly diagnosed cancer and the most common cause of cancer death throughout the globe (Ferlay et al., 2010). In Lebanon, lung cancer is among the most commonly diagnosed cancers (Shamseddine et al., 2004). The exposure to carcinogens is high in Lebanon where smoking is widespread, especially with the increasing number of people smoking Narguileh, a water pipe, (Saade et al., 2008; Waked et al., 2009) that releases carcinogen-rich smoke (Monzer et al., 2008).

Matrix metalloproteinases (MMPs) are a family of enzymes that are classified according to substrate specificity and structural similarities (Brinckerhoff et al., 2000). Their basic function is to degrade extracellular matrix and basement membrane (Egeblad and Werb, 2002). They are also involved in various cellular functions. There has been mounting evidence to support the role of MMPs in cancer progression (Kessenbrock et al., 2010). MMPs have been suggested as a key role player in cancer development including cell proliferation, apoptosis, and angiogenesis (Ye, 2000; Decock et al., 2008). MMP3, also known as stromelysin-1, is located on chromosome11q. MMP3 degrades many noncollagenous matrix components such as proteoglycans, fibronectin, laminin, and gelatin in addition to III, IV, and V collagens. It also activates interstitial proMMP1 (Nagase and Woessner, 1999).

MMP3 gene polymorphism is an insertion/deletion of an adenosine (A) at position −1171. It has two alleles; one having a run of six adenosines (6A) and the other having five adenosines (5A). Several groups have investigated the association between MMP3 promoter polymorphism and cancers including colorectal, head and neck, breast, ovarian, esophageal, bladder, liver, and renal cancer (Biondi et al., 2000; Hashimoto et al., 2004; Hirata et al., 2004; Krippl et al., 2004; Zhang et al., 2004; Kader et al., 2006; Woo et al., 2007). Further, some studies have studied the relation between MMP3 promoter polymorphism and lung cancer (Fang et al., 2005; Su et al., 2006). To the best of our knowledge, the association of MMP3 single nucleotide polymorphism (SNP) with lung cancer has not been clarified in the Lebanese population so far. Therefore, we conducted a case-control study to investigate the association between MMP3-1171(5A>6A) and lung cancer in Lebanon.

Materials and Methods

Results

Discussion

The present study is the first to examine the relationship between genetic polymorphism of MMPs and lung cancer within the Lebanese population. Our data clearly demonstrate an association between the MMP3 5A allele and lung cancer.

A recent meta-analysis (Peng et al., 2010) found that although the 6A/6A genotype may not be a risk factor for cancer in general, stratification according to smoking status lead to a different conclusion. Indeed, individuals with 6A/6A genotype had a lower risk of lung cancer if they were smokers while the nonsmokers who were 6A/6A carriers had higher risk lung cancer (Peng et al., 2010).

Moreover, in a previous study in China (Fang et al., 2005), they found that the overall genotype and allele distribution in cancer patients was not significantly different from controls. However, when results were stratified, smoking individuals with the MMP3 5A allele had a more than 1.5-fold increased risk to develop lung cancer, compared with those homozygous for 6A (Fang et al., 2005). This is in line with our study, where the majority of cases were also smokers.

However, the small sample size was a major limitation in our study. Further large-scale studies are required to confirm the suggested associations in the current study. A larger population would also allow result stratification, to make a comparison of MMP3 gene polymorphisms between smokers and nonsmokers. In this study, only two of our cases never smoked before; therefore, result stratification was not possible due to the small sample size. The identification of genetic risk factors and susceptibility gene polymorphisms in the Lebanese population is essential for better lung cancer screening, prevention, and treatment.