Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancer.

PURPOSE: Matrix metalloproteinase 9 (MMP-9) plays critical roles in cancer development and aggression. Nonsynonymous single-nucleotide polymorphisms (SNP) in the functional domain of the MMP-9 gene may influence substrate and inhibitor binding and contribute to cancer predisposition and aggression. PATIENTS AND METHODS: To test our hypothesis that common nonsynonymous SNPs, R279Q, P574R, and R668Q, in MMP-9 are associated with lung cancer development and metastasis, we conducted a case-control study of 744 patients with incident lung cancer and 747 cancer-free controls in Southeast China. Multivariate logistic regression analysis was used to calculate adjusted odds ratio (OR) and 95% confidence interval (95% CI). RESULTS: We found that compared with the 279QQ genotype, the 279RR genotype was associated with significant elevated risk of lung cancer with metastasis (adjusted OR, 1.79; 95% CI, 1.03-3.08), whereas the 574PR heterozygote and 574PP homozygote had 1.46-fold (95% CI, 0.94-2.26) and 1.69-fold elevated risk (95% CI, 1.10-2.60), respectively, compared with the 574RR genotype. When we examined the combined effect of R279Q and P574R and used the 279R and 574P as the risk alleles, a significantly increased risk of lung cancer was associated with both the genotypes containing "1 to 2 risk alleles" (adjusted OR, 2.16; 95% CI, 1.30-3.59) and containing ">2 risk alleles" (adjusted OR, 2.44; 95% CI, 1.48-4.03), and it was more pronounced in 290 lung cancer cases with metastasis [adjusted OR, 2.30 (95% CI, 1.09-4.85) for the 1 to 2 risk alleles subgroup and adjusted OR, 2.82 (95% CI, 1.35-5.88) for the >2 risk alleles subgroup], compared with those without any risk alleles. However, no overall significant associations were observed between R668Q and lung cancer risk in this study population. CONCLUSION: These findings indicate that the potentially functional polymorphisms, MMP-9 P574R and R279Q, may confer the biomarker in the occurrence and metastasis of primary lung cancer. Further functional studies including these two genetic variants are warranted to confirm our findings.

A promoter polymorphism (-77T>C) of DNA repair gene XRCC1 is associated with risk of lung cancer in relation to tobacco smoking.

X-ray repair cross complementing group 1 (XRCC1) is one of the major DNA repair proteins involved in the base-excision repair pathway. Functional Polymorphisms in the XRCC1 gene may lead to decreased DNA repair capacity and thus confer inherited predisposition to cancer risk. In this case-control study of 710 patients with incident lung cancer and 710 cancer-free controls who were frequency matched on age, sex and residential area, we genotyped a novel T>C transition at the promoter region (-77T>C) of XRCC1 and other two common non-synonymous polymorphisms (Arg194Trp and Arg399Gln) to determine their associations with risk of lung cancer. We found that compared with the -77TT wild-type homozygote, the variant genotypes were associated with significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.51; 95% confidence interval (CI)=1.17-1.94 for -77TC; OR=2.98; 95% CI=0.93-9.59 for -77CC; and OR=1.55; 95% CI=1.21-1.98 for -77TC/CC]. By contrast, no significant associations were observed between the other two exonic variants (Arg194Trp and Arg399Gln) and lung cancer risk. Furthermore, we observed a 9.82-fold increased risk (95% CI=5.66-17.02) for heavy smokers carrying the -77C variant (-77TC/CC) and a 4.07-fold increased risk (95% CI=2.85-5.81) for heavy smokers not carrying the variant. However, the interaction between the -77T>C variant and cumulative smoking was not statistically significant (P=0.1560). These findings indicate that the new XRCC1 -77T>C polymorphism may contribute to the aetiology of lung cancer. Further functional studies are warranted to elucidate the underlying molecular mechanisms of the association.