Strahlentherapie und Onkologie

, Volume 191, Issue 1, pp 59–66 | Cite as

Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

  • Sebastian Reuther
  • Silke Szymczak
  • Annette Raabe
  • Kerstin Borgmann
  • Andreas Ziegler
  • Cordula Petersen
  • Ekkehard Dikomey
  • Ulrike Hoeller
Original article
First Online:
Received:
Accepted:

Abstract

Background and purpose

The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity.

Materials and methods

Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n = 83), fibrosis (n = 123), or individual radiosensitivity (n = 123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted.

Results

With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance.

Conclusion

Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.

Keywords

Polymorphism, single nucleotide Radiotherapy Erythema Fibrosis Individual radiosensitivity 

Assoziation zwischen SNPs aus definierten Signalwegen und dem Risiko von früher oder später Toxizität und individueller Strahlenempfindlichkeit

Zusammenfassung

Hintergrund und Ziel

Für ein SNP-Netzwerk („single nucleotide polymorphism“, Einzelnukleotidpolymorphismus), welches im ROS-Signalweg, an der DNA-Reparatur und im TGFB1-Signalweg involviert ist, sollen die Bedeutung für die akute und späte Toxizität sowie die individuelle Strahlenempfindlichkeit bestimmt werden.

Material und Methoden

Nach Strahlentherapie wurden Brustkrebspatientinnen entweder hinsichtlich des Erythems (n = 83), einer Fibrose (n = 123) oder der individuellen Strahlenempfindlichkeit (n = 123) untersucht. Die 17 untersuchten SNPs sind entweder am ROS-Pathway (GSTP1, SOD2, NQO1, NOS3, XDH), bei der DNA-Reparatur (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) oder dem TGFB Signalling (SKIL, EP300, APC, AXIN1, TGFB1) beteiligt. Die Assoziation mit biologischen und klinischen Endpunkten wurde für einzelne, aber insbesondere für Kombinationen von SNPs untersucht, wobei angenommen wurde, dass ein SNPs sowohl von Vorteil als auch von Nachteil sein kann und auch gewichtet werden sollte.

Ergebnisse

Mit einer Ausnahme wurde für einen einzelnen SNP keine signifikante Assoziation identifiziert. Ebenfalls keine signifikante Assoziation wurde gefunden, wenn alle SNPs in einem Wert zusammengefasst werden, unter der Annahme, dass ein SNP immer nachteilig ist. Im Gegensatz dazu ergeben sich signifikante Assoziationen, wenn davon ausgegangen wird, dass ein SNP entweder nachteil- oder vorteilhaft sein kann. Diese Assoziationen werden noch stärker, wenn die SNPs individuell gewichtet werden. Eine detaillierte Analyse des Netzwerks ergibt, dass das Erythem und die individuelle Strahlenempfindlichkeit insbesondere durch SNPs in der DNA-Reparatur und dem TGFB1-Signalweg bestimmt werden, während SNPs im ROS-Signalweg ohne große Bedeutung sind.

Schlussfolgerung

Funktionale SNP-Netzwerke können genutzt werden, um einen Risikoscore zu bilden, der es erlaubt das Risiko für akute und späte Toxizität vorherzusagen und die zugrundeliegenden Mechanismen aufzuklären.

Schüsselwörter

Einzelnukleotidpolymorphismus Strahlentherapie Erythem Fibrose Individuelle Strahlenempfindlichkeit 
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Notes

Compliance with ethical guidelines

Acknowledgments

The authors thank Ms. Maria Omniczynski for the excellent technical assistance. This project was supported by the Deutsche Bundesministerien für Umwelt und Reaktorsicherheit (BMU, grant no. StrSch4460) as well as Bildung und Forschung (BMBFgrant no. 02NUK005B).

Conflict of interest

Reuther, S. Szymzcak, A. Raabe, K. Borgmann, A. Ziegler, C. Petersen, E. Dikmey and U. Hoeller state that there are no conflicts of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Sebastian Reuther
    • 1
  • Silke Szymczak
    • 3
    • 4
  • Annette Raabe
    • 1
  • Kerstin Borgmann
    • 1
  • Andreas Ziegler
    • 3
    • 5
  • Cordula Petersen
    • 2
  • Ekkehard Dikomey
    • 1
  • Ulrike Hoeller
    • 6
  1. 1.Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and RadiooncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Clinic of Radiotherapy and RadiooncologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  3. 3.Institute of Medical Biometry and StatisticsUniversity Medical Center Schleswig-HolsteinCampus LübeckUniversity at LübeckLübeckGermany
  4. 4.Institute of Clinical Molecular BiologyChristian-Albrechts-University KielKielGermany
  5. 5.Center for Clinical TrialsUniversity of LübeckLübeckGermany
  6. 6.Department of RadiotherapyCharité Universitätsmedizin BerlinBerlinGermany

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