Association of plasminogen-activator inhibitor 1 (PAI-1) 4G/5G gene polymorphism with survival and chemotherapy-related vascular toxicity in non-seminomatous testicular cancer (TC)

Abstract

5083 Background: High PAI-1 expression by tumor has been associated with poor prognosis in different cancer types, while high systemic PAI-1 levels may increase the risk of vascular thrombosis. We investigated whether the 4G/5G del/ins polymorphism in the PAI-1 promoter (rs1799889; 4G might lead to higher transcription), is associated with differences in survival and prevalence of cardiovascular events in TC. METHODS: Data were collected on survival and cardiovascular events (venous thromboembolism [VTE] and coronary heart disease [CHD]) of TC patients treated with standard platinum based chemotherapy from 1977-2004. PAI-1 genotype was determined from non-tumor genomic DNA by a Taqman SNP assay. Genotypes were compared for survival (Kaplan-Meier curves + log-rank and Cox-regression analysis), disease outcome (logistic regression) and prevalence of VTE and CHD (χ(2)-test). RESULTS: Data are available for 324 patients with median follow-up of 10 yrs (range 0-28). The 3 genotypes 4G/4G (n = 84), 4G/5G (n = 164), and 5G/5G (n = 76) do not differ in age and initial chemotherapy regime. However, the 4G/4G variant shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared to 4G/5G + 5G/5G (24% vs 10%; p = 0.003), as well as a decreased TC related survival compared to 4G/5G + 5G/5G (83% vs 94%; p = 0.001) with a hazard ratio of 2.68 for TC related death (95%CI 1.26-5.72; adjusted for IGCCC p = 0.011). In addition, the 4G/4G variant shows an odds ratio of 3.35 for refractory TC and early relapses (<2 yrs) (95% CI 1.48-7.58; p = 0.004). The 3 genotypes do not differ significantly in prevalence of VTE (4G/4G 11.9%, 4G/5G 8.5%, 5G/5G 7.9%; p = 0.616) and CHD during/after chemotherapy (4G/4G 6.0%; 4G/5G 4.9%; 5G/5G 2.6%; p = 0.594). CONCLUSIONS: The 4G/4G variant of the PAI-1 4G/5G gene polymorphism is associated with IGCCC poor prognosis, reduced survival and higher prevalence of refractory disease and early relapses. No effect on vascular toxicity was found. The 4G/4G variant of the PAI-1 gene may be an unfavorable prognostic factor as well as an unfavorable predictive factor for response to chemotherapy in patients with TC. No significant financial relationships to disclose.