Association of PAI‐1 gene polymorphism with survival and chemotherapy‐related vascular toxicity in testicular cancer

Abstract

High Plasminogen-Activator Inhibitor 1 (PAI-1) expression by tumors has been associated with poor prognosis in several cancer types, and high systemic PAI-1 levels with increased thrombosis risk. The authors investigated whether the germline 4G/5G deletion/insertion polymorphism in the PAI-1 promoter (rs1799889), which may influence PAI-1 expression, is associated with survival and chemotherapy-related vascular toxicity in testicular cancer (TC). Data were collected on PAI-1 4G/5G polymorphism, survival, venous thromboembolism (VTE), and coronary heart disease (CHD) for 324 non-seminomatous TC patients treated with platinum-based chemotherapy. Genotypes were compared regarding survival and disease outcome. VTE and CHD incidence were compared with adjustment for cardiovascular risk factors and prothrombotic gene polymorphisms of coagulation factors II/prothrombin (G20210A) and V (G1691A). The 4G/4G variant of PAI-1 4G/5G polymorphism shows a higher prevalence of International Germ Cell Cancer Classification (IGCCC) poor prognosis compared with 4G/5G and 5G/5G (24% vs 8% and 15%; chi-square P = .003). In addition, the 4G/4G variant shows reduced TC-related survival with a hazard ratio of 2.69 (95% CI, 1.26-5.73; P = .010) for TC-related death (adjusted for IGCCC). This is related to an increased risk for refractory disease and early relapses (odds ratio, 3.35; 95% CI, 1.48-7.59; P = .004). PAI-1 4G/5G polymorphism is not associated with VTE and CHD risk. The 4G/4G variant of PAI-1 4G/5G polymorphism may be an unfavorable prognostic as well as predictive factor for response to chemotherapy in TC patients. If confirmed, it may contribute to the identification of patients with increased risk for refractory disease.