title: Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Radiobiology & Experimental Radiooncology, Department of Radiotherapy and Radiooncology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Reuther
authors.forename: Silke
authors.initials: S
authors.lastname: Szymczak
authors.forename: Annette
authors.initials: A
authors.lastname: Raabe
authors.forename: Kerstin
authors.initials: K
authors.lastname: Borgmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Cordula
authors.initials: C
authors.lastname: Petersen
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Dikomey
authors.forename: Ulrike
authors.initials: U
authors.lastname: Hoeller
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000532:radiotherapy*; D004260:DNA Repair / Q000235:genetics*; D005260:Female; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D005858:Germany / Q000453:epidemiology; D006801:Humans; D015994:Incidence; D015810:Linkage Disequilibrium / Q000235:genetics; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011832:Radiation Injuries / Q000453:epidemiology / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D012189:Retrospective Studies; D018570:Risk Assessment / Q000379:methods; D015398:Signal Transduction / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D005819:Genetic Markers; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1