title: Association of genetic variants in apoptosis genes FAS and FASL with radiation-induced late toxicity after prostate cancer radiotherapy.
abstract: OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Department of Therapeutic Radiology and Oncology, Medical University of Graz, Auenbruggerplatz 32, 8036, Graz, Austria.
authors.forename: E-M
authors.initials: EM
authors.lastname: Thurner
authors.forename: S
authors.initials: S
authors.lastname: Krenn-Pilko
authors.forename: U
authors.initials: U
authors.lastname: Langsenlehner
authors.forename: W
authors.initials: W
authors.lastname: Renner
authors.forename: A
authors.initials: A
authors.lastname: Gerger
authors.forename: K S
authors.initials: KS
authors.lastname: Kapp
authors.forename: T
authors.initials: T
authors.lastname: Langsenlehner
mesh_terms: D000368:Aged; D000483:Alleles; D017209:Apoptosis / Q000235:genetics*; D003131:Combined Modality Therapy; D003430:Cross-Sectional Studies; D019583:Dose Fractionation, Radiation; D053222:Fas Ligand Protein / Q000235:genetics*; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic / Q000528:radiation effects; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D058958:Organs at Risk; D011110:Polymorphism, Genetic / Q000235:genetics; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy* / Q000601:surgery; D011832:Radiation Injuries / Q000235:genetics*; D011880:Radiotherapy Planning, Computer-Assisted; D018714:Radiotherapy, Adjuvant; D012007:Rectum / Q000528:radiation effects*; D012307:Risk Factors; D001743:Urinary Bladder / Q000528:radiation effects*; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D019014:fas Receptor