基质金属蛋白酶3基因多态性与非小细胞肺癌遗传易感性及淋巴结转移的关系

Correlation of Matrix Metalloproteinase-3 Polymorphism to Genetic Susceptibility and Lymph Node Metastasis of Non-small Cell Lung Cancer

背景与目的:基质金属蛋白酶(matrixmetalloproteinases,MMPs)可能通过降解细胞外基质(extracellularmatrix,ECM)和基底膜(basementmembrane,BM)参与肿瘤的侵袭和转移。MMP-3启动子区-1171bp处5A或6A单核苷酸多态性(singlenucleotidepolymorphism,SNP)可改变该基因的转录水平,从而影响MMP-3的表达。本实验目的是研究MMP-3启动子区SNP与中国北方人非小细胞肺癌(non-smallcelllungcarcinoma,NSCLC)遗传易感性及淋巴结转移的关系。方法:采用聚合酶链反应-限制性片段长度多态性分析(polymerasechainreaction-restrictionfragmentlengthpolymorphism,PCR-RFLP)方法,分析173名NSCLC患者和350名健康对照者的MMP-3启动子区SNP位点的基因型。结果:MMP-3基因型在NSCLC病例组和健康对照组的分布均符合Hardy-Weinberg平衡(P>0.05);病例组和健康对照组的6A/6A、5A/6A和5A/5A基因型频率分别为65.3%、30.6%、4.1%和67.7%、30.0%、2.3%,6A和5A等位基因频率分别为79.3%、20.7%和82.7%、17.3%,总体分布均无显著性差异(P>0.05);根据吸烟状况及病理类型分层分析发现,吸烟患者组5A等位基因频率(21.0%)显著高于健康吸烟组(12.9%)(χ2=4.81,P=0.03),携带5A/5A或5A/6A基因型可显著增高吸烟者的NSCLC发病风险(经性别。

BACKGROUND & OBJECTIVE: Matrix metalloproteinases (MMPs) might be involved in invasion and metastasis of tumors by degrading extracellular matrix (ECM) and basement membrane (BM). The 5A or 6A single nucleotide polymorphism (SNP) at the -1 171 bp site of promoter region of MMP-3 may modify the transcription and local expression of MMP-3. This study was to investigate correlation of the MMP-3 SNP with genetic susceptibility and lymph node metastasis of non-small cell lung cancer (NSCLC). METHODS: Genotypes of the MMP-3 SNP of 173 NSCLC patients and 350 healthy controls were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Distributions of the MMP-3 genotypes in both NSCLC patients and healthy controls were accorded with Hardy-Weinberg equilibrium (P>0.05). Frequencies of the 6A/6A, 5A/6A, and 5A/5A genotypes were 65.3%, 30.6%, and 4.1% in NSCLC patients, and 67.7%, 30.0%, and 2.3% in healthy controls, whereas frequencies of the 6A and 5A alleles were 79.3% and 20.7% in NSCLC patients, and 82.7% and 17.3% in healthy controls. The overall genotype and allelotype distributions among NSCLC patients and healthy controls were similar (P>0.05). However, stratified analysis found that frequency of the 5A allele was significantly higher in smoking patients than in healthy smokers (21.0% vs. 12.9%, P=0.03). Therefore, smokers with the 5A/6A or 5A/5A genotype have higher risk of developing NSCLC [age and sex adjusted odds ratio (OR) =2.07, 95% confidence interval (CI) =1.13-3.78]. When stratified by pathologic types, no significant difference in MMP-3 genotype or allelotype distribution between adenocarcinoma patients, squamous carcinoma patients and healthy controls was shown. When further stratified by lymphatic metastasis status, frequencies of the 5A allele and the 5A/5A genotype were significantly higher in NSCLC patients with lymphatic metastasis than in NSCLC patients without lymphatic metastasis (22.8% vs. 11.8%, P=0.02; 8.6% vs. 0%, P=0.02). Thus, NSCLC patients with the 5A/5A genotype have higher risk of lymphatic metastasis than NSCLC patients with the 6A/6A genotype (OR=12.38, 95% CI=0.76-202.13). CONCLUSIONS: The 5A allele of MMP-3 might be associated with the increased susceptibility to NSCLC among smokers. The 5A homozygote might increase the risk of lymphatic metastasis in NSCLC patients.