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Association of genetic variants in apoptosis genes FAS and FASL with radiation-induced late toxicity after prostate cancer radiotherapy

Zusammenhang zwischen Polymorphismen in den Apoptosegenen FAS und FASL mit strahleninduzierter Spättoxizität nach Radiotherapie des Prostatakarzinoms

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Abstract

Background and purpose

Fas ligand (FASL) triggers apoptotic cell death by cross-linking with its receptor FAS, and after irradiation, expression of FAS and FASL is increased. In the present study, we investigated the association between common polymorphisms in the genes for FAS and FASL and the risk of late side effects after radiotherapy for prostate cancer.

Patients and methods

The role of FAS (− 1377G > A, rs2234767 and − 670A > G, rs1800682) and FASL (− 844C > T, rs763110) gene polymorphisms in the development of high-grade late rectal and/or urinary toxicity (defined as late toxicity EORTC/RTOG grade ≥ 2) was analyzed in 607 prostate cancer patients treated with radiotherapy. DNA was isolated and the selected polymorphisms were determined by 5’-nuclease (TaqMan) assays.

Results

After a median follow-up time of 82 months, high-grade late rectal and/or urinary toxicity was observed in 175 patients (29.7 %). Univariate analysis revealed a significantly decreased risk of high-grade late toxicity in carriers of the FASL − 844T allele. After adjusting for covariates, patients harboring at least one − 844T allele (CT or TT genotype) remained at decreased risk of high-grade late toxicity compared with patients harboring the CC genotype [hazard ratio (HR) 0.585, 95 %CI 0.39–0.878; p = 0.010]. For patients with the − 844TT genotype, the HR was 0.404 (95 %CI 0.171–0.956; p = 0.039) in multivariate analysis. No significant associations were found for the remaining polymorphisms analyzed.

Conclusions

These results provide the first evidence that the presence of the FASL − 844T variant allele may have a protective effect against the development of high-grade late rectal and/or urinary side effects after prostate cancer radiotherapy.

Zusammenfassung

Hintergrund

Fas-Ligand (FASL) triggert durch Bindung an seinen Rezeptor FAS den apoptotischen Zelltod, desweiteren konnte nach Bestrahlung eine Überexpression von FAS und FASL beobachtet werden. Ziel der vorliegenden prospektiven Studie war die Untersuchung der Zusammenhänge von Einzelnukleotidpolymorphismen in den Genen FAS und FASL mit dem Risiko von höhergradigen Spätfolgen nach Radiotherapie des Prostatakarzinoms.

Patienten und Methoden

Assoziationen zwischen Genvarianten in FAS (− 1377G > A, rs2234767 und − 670A > G, rs1800682) und FASL (− 844C > T, rs763110) und höhergradigen rektalen und/oder urogenitalen Spätfolgen (definiert als Spättoxizität EORTC/RTOG Grad ≥ 2) wurden bei 607 Prostatakarzinompatienten untersucht. Nach DNA-Isolierung wurde die Genotypisierung der Kandidatenpolymorphismen mittels eines 5’-Nuklease-(TaqMan-)Assays durchgeführt.

Ergebnisse

Innerhalb einer medianen Nachbeobachtungszeit von 82 Monaten traten bei 175 Patienten (29,7 %) höhergradige rektale und/oder urogenitale Spätfolgen auf. In der univariaten Analyse zeigte sich ein signifikant niedrigeres Risiko für das Auftreten von höhergradigen Spätfolgen bei Trägern des − 844T-FASL-Allels. Auch die nachfolgende multivariate Analyse ergab für Träger mit zumindest einem − 844T-FASL-Allel (CT- oder TT-Genotyp) ein niedrigeres Risiko für höhergradige Spätfolgen als für Patienten mit dem CC-Genotyp (Hazard Ratio [HR] 0,585; 95 %-KI 0,39–0,878; p = 0,010). Bei Patienten mit dem − 844-TT-Genotyp lag die HR für Spätfolgen bei 0,404 (95 %-KI 0,171–0,956; p = 0,039). Für die übrigen Genpolymorphismen konnten keine signifikanten Zusammenhänge gefunden werden.

Schlussfolgerung

Aus den Ergebnissen geht hervor, dass das Vorhandensein des − 844T-FASL-Allels möglicherweise einen protektiven Effekt hinsichtlich des Auftretens von Spätfolgen nach Radiotherapie bei Prostatakarzinompatienten mit sich bringt.

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Compliance with ethical guidelines

Conflict of interest. E.-M. Thurner, S. Krenn-Pilko, U. Langsenlehner, W. Renner, A. Gerger, K.S. Kapp, and T. Langsenlehner state that there are no conflicts of interest. All studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form). Informed consent was obtained from all patients included in studies.

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Authors and Affiliations

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

    E.-M. Thurner, S. Krenn-Pilko, K.S. Kapp & T. Langsenlehner MD

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

    U. Langsenlehner

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

    W. Renner

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

    A. Gerger

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  1. E.-M. Thurner
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Correspondence to T. Langsenlehner MD.

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Thurner, EM., Krenn-Pilko, S., Langsenlehner, U. et al. Association of genetic variants in apoptosis genes FAS and FASL with radiation-induced late toxicity after prostate cancer radiotherapy. Strahlenther Onkol 190, 304–309 (2014). https://doi.org/10.1007/s00066-013-0485-0

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  • DOI: https://doi.org/10.1007/s00066-013-0485-0

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