Wang Yan, Ye Yuanqing, Lin Jie, Meyer Larissa, Wu Xifeng, Lu Karen, Liang Dong
Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Mol Carcinog. 2015 Jun;54(6):430-9. doi: 10.1002/mc.22111. Epub 2013 Nov 19.
Ovarian cancer is one of the leading female cancers in the United States. Challenges remain in early diagnosis of this deadly disease. Matrix metalloproteinases (MMPs) family genes are paradoxically involved in cancer promotion and suppression. We hypothesize that genetic variants in MMP genes are associated with ovarian cancer development, so they could be potential markers for ovarian cancer diagnosis and prognosis. In this study of 417 ovarian cancer cases and 417 healthy controls, we genotyped a comprehensive panel of 266 single nucleotide polymorphisms (SNPs) in 23 MMP genes and analysed their associations with ovarian cancer risk, overall survival and treatment response in ovarian cancer cases who received platinum-based chemotherapy with surgery. In the analysis on 339 Caucasian cases and 349 Caucasian controls, 4 SNPs were significantly associated with cancer risk. The most significant association was observed for rs2292730 (OR = 2.03, 95% CI = 1.39-2.96, P = 0.0002). Classification and regression tree analysis identified four terminal nodes with differential risk of ovarian cancer. Thirty-four SNPs were significantly associated with overall survival and four of which showed significant association with response to chemotherapy. Unfavourable genotype analysis of top SNPs on overall risk of death showed significant gene-dosage effect, survival tree analysis differentiated patients into distinct risk groups based on their genetic profiles with median survival times (MSTs) ranging from 17.7 to 151.7 months. In conclusion, our results suggest that genetic variants in MMP pathway genes may modulate the risk and clinical outcomes of ovarian cancer, both individually and jointly.
卵巢癌是美国主要的女性癌症之一。对这种致命疾病的早期诊断仍存在挑战。基质金属蛋白酶（MMPs）家族基因在癌症的促进和抑制过程中有着矛盾的作用。我们假设MMP基因中的遗传变异与卵巢癌的发生有关，因此它们可能是卵巢癌诊断和预后的潜在标志物。在这项对417例卵巢癌病例和417名健康对照的研究中，我们对23个MMP基因中的266个单核苷酸多态性（SNP）进行了全面的基因分型，并分析了它们与接受铂类化疗联合手术的卵巢癌病例的卵巢癌风险、总生存期和治疗反应之间的关联。在对339例白种人病例和349名白种人对照的分析中，4个SNP与癌症风险显著相关。rs2292730的关联最为显著（OR = 2.03，95% CI = 1.39 - 2.96，P = 0.0002）。分类和回归树分析确定了四个卵巢癌风险不同的终末节点。34个SNP与总生存期显著相关，其中4个与化疗反应显著相关。对总体死亡风险最高的SNP进行的不利基因型分析显示出显著的基因剂量效应，生存树分析根据患者的基因谱将其分为不同的风险组，中位生存期（MSTs）从17.7个月到151.7个月不等。总之，我们的结果表明，MMP通路基因中的遗传变异可能单独或共同调节卵巢癌的风险和临床结局。
