title: SNP in TXNRD2 associated with radiation-induced fibrosis: a study of genetic variation in reactive oxygen species metabolism and signaling.
abstract: OBJECTIVE
  The aim of the study was to identify noninvasive markers of treatment-induced side effects. Reactive oxygen species (ROS) are generated after irradiation, and genetic variation in genes related to ROS metabolism might influence the level of radiation-induced adverse effects (AEs).
  
  
  METHODS
  92 breast cancer (BC) survivors previously treated with hypofractionated radiation therapy were assessed for the AEs subcutaneous atrophy and fibrosis, costal fractures, lung fibrosis, pleural thickening, and telangiectasias (median follow-up time 17.1 years). Single-nucleotide polymorphisms (SNPs) in 203 genes were analyzed for association to AE grade. SNPs associated with subcutaneous fibrosis were validated in an independent BC survivor material (n=283). The influence of the studied genetic variation on messenger ribonucleic acid (mRNA) expression level of 18 genes previously associated with fibrosis was assessed in fibroblast cell lines from BC patients.
  
  
  RESULTS
  Subcutaneous fibrosis and atrophy had the highest correlation (r=0.76) of all assessed AEs. The nonsynonymous SNP rs1139793 in TXNRD2 was associated with grade of subcutaneous fibrosis, the reference T-allele being more prevalent in the group experiencing severe levels of fibrosis. This was confirmed in another sample cohort of 283 BC survivors, and rs1139793 was found significantly associated with mRNA expression level of TXNRD2 in blood. Genetic variation in 24 ROS-related genes, including EGFR, CENPE, APEX1, and GSTP1, was associated with mRNA expression of 14 genes previously linked to fibrosis (P≤.005).
  
  
  CONCLUSIONS
  Development of subcutaneous fibrosis can be associated with genetic variation in the mitochondrial enzyme TXNRD2, critically involved in removal of ROS, and maintenance of the intracellular redox balance.
authors.affiliation: Department of Genetics, Institute for Cancer Research, OUS Radiumhospitalet, Oslo, Norway. hege.edvardsen@rr-research.no
authors.forename: Hege
authors.initials: H
authors.lastname: Edvardsen
authors.forename: Hege
authors.initials: H
authors.lastname: Landmark-Høyvik
authors.forename: Kristin V
authors.initials: KV
authors.lastname: Reinertsen
authors.forename: Xi
authors.initials: X
authors.lastname: Zhao
authors.forename: Grethe Irene
authors.initials: GI
authors.lastname: Grenaker-Alnæs
authors.forename: Daniel
authors.initials: D
authors.lastname: Nebdal
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Olaug
authors.initials: O
authors.lastname: Rødningen
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Borresen-Dale
authors.forename: Sophie D
authors.initials: SD
authors.lastname: Fosså
authors.forename: Vessela N
authors.initials: VN
authors.lastname: Kristensen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000532:radiotherapy*; D019583:Dose Fractionation, Radiation; D005260:Female; D005355:Fibrosis; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D010994:Pleura / Q000528:radiation effects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011832:Radiation Injuries / Q000235:genetics* / Q000378:metabolism; D017564:Radiation Pneumonitis / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012867:Skin / Q000528:radiation effects; D017741:Survivors; D013684:Telangiectasis / Q000235:genetics; D054482:Thioredoxin Reductase 2 / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; C516127:TXNRD2 protein, human; D054482:Thioredoxin Reductase 2