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)

E. C. de Haas, N. Zwart, C. Meijer, H. M. Boezen, A. J. Suurmeijer, J. van der Meer, H. J. Hoekstra, F. E. van Leeuwen, D. T. Sleijffer, J. A. Gietema

OnderzoeksoutputAcademicpeer review


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.

Originele taal-2English
Pagina's (van-tot)5083
Aantal pagina's1
TijdschriftJournal of clinical oncology : official journal of the American Society of Clinical Oncology
Nummer van het tijdschrift15_suppl
StatusPublished - mei-2009

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