title: PAI-1 -675 4G/5G polymorphism as a prognostic biomarker in breast cancer.
abstract: 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.
authors.affiliation: Division of Molecular Genetic Epidemiology C050, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
authors.forename: Haixin
authors.initials: H
authors.lastname: Lei
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Robert
authors.initials: R
authors.lastname: Johansson
authors.forename: Andrea
authors.initials: A
authors.lastname: Altieri
authors.forename: Kerstin
authors.initials: K
authors.lastname: Enquist
authors.forename: Roger
authors.initials: R
authors.lastname: Henriksson
authors.forename: Per
authors.initials: P
authors.lastname: Lenner
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D008957:Models, Genetic; D009362:Neoplasm Metastasis; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011336:Probability; D011379:Prognosis; D016896:Treatment Outcome; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D014568:Urokinase-Type Plasminogen Activator