BMC Cancer 2007, 7:187 http://www.biomedcentral.com/1471-2407/7/187 Table 5: Multivariate analysis of factors affecting OSCC A Results of factors affecting OSCC 2G+ 0.83 2.30 Age 0.90 2.47 B Results showing the alleles independently associated with OSCC (adjusted for age and gender). β coefficient β coefficient 0.782 0.907 OR OR 2.187 2.476 95% CI of OR (1.15–4.58) (1.47–4.14) 95% CI of OR (1.06–4.51) (1.20–5.13) 0.0180 0.0006 p p 0.034 0.015 Allele 1G/2G 2G/2G A: 2G+ : 2G- = 0, 2G+ = 1 Age : <45 = 0, 45 = 1 B: With adjustment for age and gender Alleles are included as multinomial variables with categorical coding in reference to 1G/1G allele. % concordance = 74.9%. Hosmer-Lemeshow Goodness-of-fit test: χ2 test = 0.996 ; p = 0.998 and presence of the MMP-1 2G allele (i.e., 2G/2G or 1G/ 2G) are independently involved in onset of OSCC. In fact, it was clarified that the significance of the presence of the MMP-1 2G allele was lower in the subject group 45 years old or older (p = 0.238, OR = 1.65, 95% CI = 0.75–3.55), and that the impact of the allele was highly significant in the younger group, which was under 45 years old (p = 0.014, OR = 9.67, 95% CI = 1.20–78.15) (data not shown). As concrete causes of OSCC, mainly tobacco smoking and alcohol usage and, in some cases, viral infections have attracted attention as environmental causative factors [25,27]. It has been suggested that tobacco smoking and alcohol usage alone may not explain the mechanism of the entire early onset of OSCC, because the duration of exposure to these risk factors in young OSCC patients is shorter than in the older group, and also because there are some cases with stable incidence that have no known risk factors [28]. The association with smoking and habitual drinking has been supported as the risk factors of OSCC, which generally shows a higher incidence in older age, but other investigators believe that the mechanism of the early onset OSCC is fundamentally different from that of eld- erly onset OSCC [25]. Cao et al. considered the relation- ship with smoking as a behavioral risk factor and the MMP-1 2G allele as a genetic risk factor in the OSCC group [23]. In lung cancer, it has been similarly shown that a genetic factor of the MMP-1 promoter 2G allele increases the risk of cancer that occurs in a tobacco-usage- dependent manner only in cases with a history of tobacco use. These reports support the role of MMP-1 promoter polymorphism as an endogenous background factor, in contrast to exogenous environmental factors [15]. How- ever, no evidence to support a notion of synergistic inter- actions between risk factors, such as habitual smoking and drinking and MMP-1 promoter polymorphism in OSCC cases, was shown in this study. Further investiga- tions with regard to frequency and duration of exposure are required to consider interactions between environ- mental factors and multiple genetic background factors. Examples are known of malignant neoplasms caused by genetic factors, for example, mutations in RB in Retino- blastoma [29], p53 in Li-Fraumeni Syndrome [30], and APC in familial adenomatous polyposis [31]. There are also reports of mutations in BRCA1 and BRCA2, which affect familial breast cancer occurrence, though their pen- etrance is low [32]. These are neoplasms that are all caused by loss-of-function mutations in molecules func- tionally classified as tumor-suppressor genes, and they are characterized by familial, juvenile or young onset and may be multicentric or bilateral. Although incidents are rare in the population, they are examples of germline mutations that directly involve heterofamilial tumorigen- esis. By contrast, the MMP-1 promoter 2G allele is a genetic polymorphism that exists at the high allele frequency of 80% to 90% in the general population. It is possible to call this a hereditary trait that is shared among races or humans in general. Other genetic factors that are classified into similar polymorphism as MMP-1 have also been reported, such as Cyclin D1 (CCND1) in head and neck squamous cell carcinoma (HNSCC) and colorectal cancer [33,34], xeroderma pigmentosum complementary group D (XPD), DNA damage binding protein 2 (DDB2), and MMP-9 in lung cancer [35-37]. Similar to the effects of mutations in tumor suppressor genes, diversity in gene expression level and molecular structure caused by genetic polymorphisms affect monitoring and repair mechanism of DNA replication, as well as control of the cell cycle, ulti- mately resulting in genetic instability. The common mechanism of carcinogenesis caused by those genetic fac- Page 6 of 9 (page number not for citation purposes)