BMC Cancer 2007, 7:187 http://www.biomedcentral.com/1471-2407/7/187 tors is an elevated carcinogenic risk due to this genetic instability. As examples of genetic polymorphisms that affect onset age of cancers other than that examined in this study, some reports discuss MMP-1 and DDB2 in lung cancer [15,36], and CCND1 in HNSCC and colorectal cancer [33,34]. These genetic factors, on the other hand, are present in patients with cancer as well as in the general population at certain frequencies. Therefore, it is hard to conclude that these genetic factors are the primary factors in early onset carcinogenesis, unlike germline single-gene mutations in Rb and APC that induce juvenile or early onset of cancers with high penetrance. Aging brings expo- sure to various carcinogenic factors and is associated with inevitable accumulation of genetic and epigenetic modifi- cations of genes. These accumulations interact synergisti- cally with biological background factors on the host side, and consequently cancer may develop [26,38]. It seems that inherited genetic factors play a larger role in develop- ment of early onset cancer that has undergone a relatively short duration of exposure to carcinogen through envi- ronment and lifestyle habits. Therefore, it is conceivable that the impact of these genetic factors would appear more directly in younger than in older cases, although we still expect a synergistic involvement of various environ- mental and genetic factors. Nevertheless, because of the disappearance ofthe MMP-1 1G allele distribution observed in the OSCC cases with a clear boundary under the age of 45 years, the MMP-1 promoter 2G allele should be recognized as an essential genetic precondition for the development of early onset OSCC. It is said that an onset age of 45 years and younger accounts for about 6% of OSCC cases [27]. It should be noted that in this study we found that the tongue was the primary site in 25 cases (86.2%) of 29 early onset OSCC cases in individuals under 45 years old. This primary site was obviously different from that in patients 45 years old and older in whom we noted 57 cases of tongue cancer (40.4%) out of 141 OSCC cases. Similar tendencies have been reported in previous studies [39,40]. These findings suggest the possibility that each primary tumor sites in the oral cavity may be associated with differences in cancer susceptibility, specific carcinogenic stimulation, or genetic background. However, no environmental or genetic fac- tors specific to a particular site of the oral mucosa have been identified for OSCC. It is conceivable that it would be important to carry out further investigations on genetic and environmental risk factors for each anatomical site of the oral regions, though we are not able to discuss this aspect of OSCC because the number of cases was inade- quate in this study. Conclusion The number of cases in this study was relatively small; therefore, the conclusions may still be contingent upon confirmation in a larger study. To evaluate the conclusive impact of MMP-1 on OSCC risk, a sufficiently large number of cases or consistency among results from multi- ple age adjusted studies would be needed. Furthermore, although the MMP-1 promoter SNP-based determination of OSCC susceptibility has the potential to become a use- ful clinical tool, it is necessary to add a greater diversity of information for practical use. In the future, improvements in diagnosis of susceptibility and clinical application could become possible by incorporating multiple genetic and environmental risk factors into the prediction model for cancer occurrence. Information about the risk of vari- ous types of malignant neoplasm as well as OSCC is use- ful for prevention and early detection of cancer or for monitoring of postoperative recurrence. A diagnostic sys- tem for evaluating cancer risk is vital not only for improvement in treatment techniques but also as a theo- retical foundation to build strategies for cancer preven- tion. Abbreviations Matrix metalloproteinase (MMP), single nucleotide poly- morphism (SNP), oral squamous cell carcinoma (OSCC), odds ratio (OR), 95% Confidence Intervals (95% CI), receiver operating characteristic curve (ROC), head and neck squamous cell carcinoma (HNSCC). Competing interests The author(s) declare that they have no competing inter- ests. Authors' contributions RN, MN participated in the design of the study. RN, MN and AAN drafted and wrote the manuscript. NK partici- pated in the statistical analysis. RN, MN and AAN partici- pated in the production of genotype data. RN, MN, KK, MO and HK participated in the acquisition and interpre- tation of data. RN, MI, HF, TK and AAN participated in the experimental studies. RN, MN, AAN, HH and SS carried out the clinical studies. SC, HY and RT participated in the review of the study. All authors read and approved the final manuscript. Acknowledgements The authors thank the staff of the Division of Dental Clinic and Oral Sur- gery of Nagaoka Red Cross Hospital for their contribution in collecting samples and the clinical data set. This investigation was supported by grants from the Japan Society for the Promotion of Science (Grants-in-Aid for Sci- entific Research; no. 12791235 and no. 18592171). References 1. 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