State Key Laboratory of Genetic Engineering, Fudan-VARI Genetic Epidemiology Center and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, 200433, People's Republic of China.
J Cancer Res Clin Oncol. 2013 Sep;139(9):1433-47. doi: 10.1007/s00432-013-1446-9. Epub 2013 May 5.
A variety of studies have been performed to elucidate the polymorphisms in promoter regions of matrix metalloproteinases (MMPs) associated with the risk of digestive cancers, and yet, results remain conflicting and heterogeneous. Thus, we undertook a systematic meta-analysis to determine the genetic susceptibility of MMPs to digestive cancers.
A computerized literature search was conducted in databases of PubMed, Embase, and ISI Web of Knowledge till October 2012 for any MMP genetic association study in oral squamous, gastric, esophageal, and colorectal carcinomas. Odds ratios (OR) and 95 % confidence interval (CI) were estimated for each gene under dominant and recessive models, and the heterogeneity between studies was assessed using Q test and I (2) value. Overall and subgroup analysis according to anatomical sites and ethnicity was carried out. Statistical analysis was performed with Review Manager 5.0.
A total of 40 eligible publications with 68 comparisons were included in this study. For MMP1 nt-1607, individuals with 2G state could increase risk of digestive cancers in total analysis (dominant: OR = 1.31, 95 % CI = 1.16-1.48, P < 0.00001; recessive: OR = 1.29, 95 % CI = 1.11-1.50, P = 0.0009). In the subgroup of tumor sites, significant associations were also observed in esophageal cancer and colorectal cancer under both genetic models. For MMP2 nt-1306, CT or TT carriers performed significant protection against digestive cancer in the dominant model (OR = 0.69, 95 % CI = 0.55-0.85, P = 0.0007) of the overall. In the subgroup analysis, significant association was found in esophageal cancer, with borderline effects in gastric cancer and oral squamous cell carcinoma. For MMP7 -181 A/G, significant association was observed under two genetic models in the overall (dominant: OR = 1.26, 95 % CI = 1.10-1.43, P = 0.0009; recessive: OR = 1.33, 95 % CI = 1.11-1.60, P = 0.002) and in the individual cancer subgroup of esophageal cancer and gastric cancer. For MMP9 -1,562 C/T, a borderline effect was found with digestive cancers in the total and stratified analysis of the colorectal cancer under dominant model. No association was observed in either the overall or subgroup analysis for MMP3 -1,171 5A/6A.
Our meta-analysis demonstrated the fact that polymorphisms in promoter regions of MMP genes might be related to the susceptibility of digestive cancers, with cancer development for MMP1 and MMP7, and a protection against cancer for MMP2 and MMP9. Further evidences with adequate sample sizes need to be conducted.
已经进行了各种研究来阐明与消化癌症风险相关的基质金属蛋白酶 (MMPs) 启动子区域的多态性，但结果仍然存在冲突和异质性。因此，我们进行了系统的荟萃分析，以确定 MMPs 对消化癌症的遗传易感性。
在 PubMed、Embase 和 ISI Web of Knowledge 数据库中进行了计算机文献检索，以查找任何 MMP 遗传关联研究，包括口腔鳞状细胞癌、胃癌、食管癌和结直肠癌。使用优势和隐性模型估计每个基因的优势比 (OR) 和 95%置信区间 (CI)，并使用 Q 检验和 I (2) 值评估研究之间的异质性。根据解剖部位和种族进行了总体和亚组分析。使用 Review Manager 5.0 进行统计分析。
这项研究共纳入了 40 项符合条件的出版物，涉及 68 项比较。对于 MMP1 nt-1607，2G 状态的个体在总体分析中可能会增加消化癌症的风险（显性：OR=1.31，95%CI=1.16-1.48，P<0.00001；隐性：OR=1.29，95%CI=1.11-1.50，P=0.0009）。在肿瘤部位的亚组中，在两种遗传模型下，食管癌和结直肠癌也观察到了显著的相关性。对于 MMP2 nt-1306，在显性模型中（OR=0.69，95%CI=0.55-0.85，P=0.0007），CT 或 TT 携带者对消化癌症具有显著的保护作用。在亚组分析中，在食管癌中发现了显著的相关性，在胃癌和口腔鳞状细胞癌中存在边缘效应。对于 MMP7-181 A/G，在总体（显性：OR=1.26，95%CI=1.10-1.43，P=0.0009；隐性：OR=1.33，95%CI=1.11-1.60，P=0.002）和食管癌和胃癌的个体癌症亚组中，在两种遗传模型下均观察到了显著的相关性。对于 MMP9-1，562 C/T，在显性模型下，在结直肠癌的总体和分层分析中，与消化癌症有边缘效应。在总体或亚组分析中，均未观察到 MMP3-1，171 5A/6A 与消化癌症有关。
我们的荟萃分析表明，MMP 基因启动子区域的多态性可能与消化癌症的易感性有关，MMP1 和 MMP7 与癌症的发生有关，而 MMP2 和 MMP9 则对癌症有保护作用。需要进一步进行具有足够样本量的证据。
