Lei Haixin, Hemminki Kari, Johansson Robert, Altieri Andrea, Enquist Kerstin, Henriksson Roger, Lenner Per, Försti Asta
Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Breast Cancer Res Treat. 2008 May;109(1):165-75. doi: 10.1007/s10549-007-9635-3. Epub 2007 Jul 7.
Extracellular matrix degradation, mediated by the urokinase plasminogen activation (uPA) system, is a critical step in tumor invasion and metastasis. High tumor levels of uPA and its inhibitor PAI-1 have been correlated with poor prognosis in breast cancer. We examined whether genetic variation in the genes of the uPA system affect breast cancer susceptibility and prognosis. We genotyped eight potentially functional single nucleotide polymorphisms (SNPs) in six genes of the uPA system in 959 Swedish breast cancer patients with detailed clinical data and up to 15 years of follow-up together with 952 matched controls. We used the unconditional logistic regression models to evaluate the associations between genotypes and breast cancer risk and tumor characteristics. The Kaplan-Meier method was used to estimate the survival probabilities; the log-rank test was used to test differences between subgroups. None of the SNPs conferred an increased breast cancer risk, but correlation with some traditional prognostic factors was observed for several SNPs. Most importantly, we identified the -675 4G/5G SNP in the PAI-1 gene as a promising prognostic biomarker for breast cancer. Compared to the 4G/4G and 4G/5G genotypes 5G/5G homozygosity correlated significantly with worse survival (RR 2.04, 95% CI 1.45-2.86, P<0.001), especially in patients with more aggressive tumors. 5G/5G homozygotes were also the group with worse survival among lymph node negative cases. Our finding suggests that genotyping PAI-1 -675 4G/5G may help in clinical prognosis of breast cancer.
由尿激酶型纤溶酶原激活（uPA）系统介导的细胞外基质降解是肿瘤侵袭和转移的关键步骤。乳腺癌中uPA及其抑制剂PAI-1的高肿瘤水平与不良预后相关。我们研究了uPA系统基因的遗传变异是否影响乳腺癌的易感性和预后。我们对959名有详细临床数据且随访长达15年的瑞典乳腺癌患者以及952名匹配对照，对uPA系统六个基因中的八个潜在功能性单核苷酸多态性（SNP）进行了基因分型。我们使用无条件逻辑回归模型来评估基因型与乳腺癌风险和肿瘤特征之间的关联。采用Kaplan-Meier方法估计生存概率；采用对数秩检验来检验亚组之间的差异。没有一个SNP增加乳腺癌风险，但观察到几个SNP与一些传统预后因素相关。最重要的是，我们将PAI-1基因中的-675 4G/5G SNP确定为一种有前景的乳腺癌预后生物标志物。与4G/4G和4G/5G基因型相比，5G/5G纯合性与较差的生存率显著相关（风险比2.04，95%置信区间1.45 - 2.86，P<0.001），尤其是在肿瘤侵袭性更强的患者中。5G/5G纯合子也是淋巴结阴性病例中生存率较差的组。我们的发现表明，对PAI-1 -675 4G/5G进行基因分型可能有助于乳腺癌的临床预后评估。
