Lei Haixin, Hemminki Kari, Altieri Andrea, Johansson Robert, Enquist Kerstin, Hallmans Göran, Lenner Per, Försti Asta
Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, D-69120 Heidelberg, Germany.
Breast Cancer Res Treat. 2007 May;103(1):61-9. doi: 10.1007/s10549-006-9345-2. Epub 2006 Oct 11.
The importance of matrix metalloproteinases and their inhibitors in tumor progression is well documented. We wanted to investigate if single nucleotide polymorphisms (SNPs) in the promoter regions of these genes are associated with susceptibility to or progression of breast cancer. In this, so far largest case-control study, we genotyped eight SNPs in the MMP1, MMP2, MMP3, MMP9, MMP13, RECK and TIMP3 genes in a well-characterized breast cancer series of 959 cases and 952 controls from Sweden. Even though we did not correct for multiple comparisons, only a few associations were noted. We observed a moderately increased risk for the TT homozygotes of the MMP9-1562 C/T SNP (OR 1.88, 95% CI 0.97-3.63) and for the C allele carriers of the TIMP3-1296 T/C SNP (OR 1.25, 95% CI 1.05-1.50). In the survival analysis, only the TC heterozygotes of the RECK-420 T/C SNP showed a better survival compared to the TT homozygotes (P = 0.02 in all cases and P = 0.03 in lymph node negative cases). None of the other SNPs conferred an increased breast cancer risk, nor did they correlate with survival. A combination of the -585 TT homozygosity in the RECK gene and the -1296 TT homozygosity in the TIMP3 gene correlated with estrogen and progesterone receptor status (OR 1.81, 95% CI 1.03-3.21 and OR 2.10, 95% CI 1.18-3.86, respectively), and a combination of the -1306 TT homozygosity in the MMP2 gene and the -1562 CC homozygosity in the MMP9 gene with progesterone receptor status (OR 2.34, 95% CI 1.08-5.08). Although our study suggests some correlations between the studied SNPs and the progression of breast cancer, the rarity of the risk genotypes limits their usefulness in the clinic.
基质金属蛋白酶及其抑制剂在肿瘤进展中的重要性已有充分文献记载。我们想要研究这些基因启动子区域的单核苷酸多态性（SNP）是否与乳腺癌的易感性或进展相关。在这项迄今为止最大规模的病例对照研究中，我们对来自瑞典的959例特征明确的乳腺癌患者和952例对照的MMP1、MMP2、MMP3、MMP9、MMP13、RECK和TIMP3基因中的8个SNP进行了基因分型。尽管我们未对多重比较进行校正，但仅发现了少数关联。我们观察到MMP9 - 1562 C/T SNP的TT纯合子（比值比1.88，95%可信区间0.97 - 3.63）以及TIMP3 - 1296 T/C SNP的C等位基因携带者（比值比1.25，95%可信区间1.05 - 1.50）的风险适度增加。在生存分析中，与TT纯合子相比，只有RECK - 420 T/C SNP的TC杂合子显示出更好的生存率（所有病例中P = 0.02，淋巴结阴性病例中P = 0.03）。其他SNP均未增加乳腺癌风险，也与生存率无关。RECK基因的 - 585 TT纯合性与TIMP3基因的 - 1296 TT纯合性的组合与雌激素和孕激素受体状态相关（分别为比值比1.81，95%可信区间1.03 - 3.21和比值比2.10，95%可信区间1.18 - 3.86），MMP2基因的 - 1306 TT纯合性与MMP9基因的 - 1562 CC纯合性的组合与孕激素受体状态相关（比值比2.34，95%可信区间1.08 - 5.08）。尽管我们的研究表明所研究的SNP与乳腺癌进展之间存在一些相关性，但风险基因型的罕见性限制了它们在临床中的实用性。
