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Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients

Die Bedeutung von VEGF-Genpolymorphismen und -Haplotypen für die Entwicklung von radiogenen Spätfolgen bei Prostatakarzinompatienten

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Abstract

Background and Purpose

Vascular endothelial growth factor (VEGF) is an important determinant of microvascular permeability and angiogenesis and has been shown to be up-regulated during the late phase of radiation injury. The present prospective study was performed to evaluate the role of VEGF gene polymorphisms and haplotypes in the development of radiation-induced late side effects in prostate cancer patients.

Patients and Methods

The association of VEGF gene polymorphisms and haplotypes with high-grade late rectal or urinary toxicity (defined as late toxicity EORTC/RTOG ≥2) was analyzed using 493 prostate cancer patients from the Austrian PROCAGENE study treated with definitive radiotherapy. Seven candidate polymorphisms in the VEGF gene were selected and determined by 5’-nuclease (TaqMan) assays.

Results

Within a median follow-up time of 48 months, 42 patients (8.6%) developed high-grade late rectal and 47 patients (9.6%) urinary toxicity, respectively. In a Kaplan–Meier analysis, carriers of the VEGF -7C > T polymorphism were at increased risk of high-grade late rectal toxicity (p = 0.003) and in a multivariate analysis including clinical and dosimetric parameters as potential confounders the VEGF -7C > T polymorphism remained a significant predictor (HR = 2.8, 95% CI 1.349–5.813; p = 0.006). Furthermore, the ATTGT haplotype formed by five polymorphisms upstream of the coding sequence demonstrated a significant association with late rectal toxicity grade ≥2 (p = 0.001). No significant associations were found for the remaining polymorphisms and haplotypes.

Conclusion

We conclude that genetic variants in the VEGF gene may influence the risk of high-grade late rectal toxicity after definitive radiotherapy for prostate cancer.

Zusammenfassung

Hintergrund

Vascular endothelial growth factor (VEGF) ist ein wichtiger Regulator der Gefäßpermeabilität und Angiogenese, und in der chronischen Strahlenreaktionsphase wurde die Hochregulation von VEGF gezeigt. Ziel der vorliegenden prospektiven Studie war die Analyse des Zusammenhangs von VEGF-Genpolymorphismen und -Haplotypen mit dem Auftreten von radiogenen Spätfolgen bei Prostatakarzinompatienten.

Patienten und Methoden

Der Zusammenhang zwischen VEGF-Genpolymorphismen und -Haplotypen und höhergradigen rektalen und urogenitalen Spätfolgen (definiert als Spättoxizität EORTC/RTOG ≥2) wurde bei 493 Prostatakarzinompatienten der PROCAGENE-Studie, die einer definitiven Strahlentherapie unterzogen wurden, untersucht. 7 Kandidatenpolymorphismen wurden ausgewählt und mittels 5´-Nuklease-Assays (TaqMan) analysiert.

Ergebnisse

Während einer medianen Nachbeobachtungszeit von 48 Monaten entwickelten 42 Patienten (8,6%) höhergradige rektale und 47 Patienten (9,6%) urogenitale Nebenwirkungen. In der Kaplan-Meier-Analyse zeigten Träger des VEGF -7C > T-Poly-morphismus ein erhöhtes Risiko für höhergradige rektale Spätfolgen (p = 0,003; Abbildung 2) und in der multivariaten Analyse, in welche klinische und dosimetrische Faktoren eingeschlossen wurden, blieb der VEGF -7C > T-Polymorphismus ein signifikanter Prediktor (HR = 28; 95%-CI 1,349–5,813; p = 0,006, Tabelle 4). Zusätzlich zeigte sich für den ATTGT-Haplotyp, bestehend aus 5 vor der kodierenden Sequenz liegenden Polymorphismen, eine signifikante Assoziation mit höhergradiger rektaler Spättoxizität (p = 0,001; Abbildung 3). Keine signifikanten Assoziationen wurden für die übrigen untersuchten Polymorphismen und Haplotypen gefunden (Tabellen 3 und 4).

Schlussfolgerung

Die vorliegenden Daten zeigen, dass Varianten im VEGF-Gen möglicherweise das Auftreten von höhergradigen rektalen Spätfolgen nach definitiver Radiotherapie des Prostatakarzinoms beeinflussen.

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Authors and Affiliations

  1. Department of Therapeutic Radiology and Oncology, Medical University of Graz, Graz, Austria

    Tanja Langsenlehner MD, Eva-Maria Thurner & Karin S. Kapp

  2. Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

    Wilfried Renner

  3. Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria

    Armin Gerger & Günter Hofmann

  4. Division of Internal Medicine, GKK Outpatient Department, Graz, Austria

    Uwe Langsenlehner

  5. Department of Therapeutic Radiology and Oncology, Medical University of Graz, Auenbruggerplatz 32, 8036, Graz, Austria

    Tanja Langsenlehner MD

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  1. Tanja Langsenlehner MD
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Correspondence to Tanja Langsenlehner MD.

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Langsenlehner, T., Renner, W., Gerger, A. et al. Impact of VEGF gene polymorphisms and haplotypes on radiation-induced late toxicity in prostate cancer patients. Strahlenther Onkol 187, 784–791 (2011). https://doi.org/10.1007/s00066-011-1106-4

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  • DOI: https://doi.org/10.1007/s00066-011-1106-4

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