title: Genetic predictors of acute toxicities related to radiation therapy following lumpectomy for breast cancer: a case-series study.
abstract: BACKGROUND
  The cytotoxic effects of radiation therapy are mediated primarily through increased formation of hydroxyl radicals and reactive oxygen species, which can damage cells, proteins and DNA; the glutathione S-transferases (GSTs) function to protect against oxidative stress. We hypothesized that polymorphisms encoding reduced or absent activity in the GSTs might result in greater risk for radiation-associated toxicity.
  
  
  METHODS
  Women receiving therapy in radiation units in Germany following lumpectomy for breast cancer (1998-2001) provided a blood sample and completed an epidemiological questionnaire (n = 446). Genotypes were determined using Sequonom MALDI-TOF (GSTA1, GSTP1) and Masscode (GSTM1, GSTT1). Biologically effective radiotherapy dose (BED) was calculated, accounting for differences in fractionation and overall treatment time. Side effects considered were grade 2c and above, as classified using the modified Common Toxicity Criteria. Predictors of toxicity were modelled using Cox regression models in relation to BED, with adjustment for treating clinic, photon field, beam energy and boost method, and potential confounding variables.
  
  
  RESULTS
  Low activity GSTP1 genotypes were associated with a greater than twofold increase in risk for acute skin toxicities (adjusted hazard ratio 2.28, 95% confidence interval 1.04-4.99). No associations were noted for the other GST genotypes.
  
  
  CONCLUSIONS
  These data indicate that GSTP1 plays an important role in protecting normal cells from damage associated with radiation therapy. Studies examining the effects of GSTP1 polymorphisms on toxicity, recurrence and survival will further inform individualized therapeutics based on genotypes.
authors.affiliation: Department of Epidemiology, Division of Cancer Prevention and Population Science, Roswell Park Cancer Institute, Buffalo, New York, USA. christine.ambrosone@roswellpark.org
authors.forename: Christine B
authors.initials: CB
authors.lastname: Ambrosone
authors.forename: Chunqiao
authors.initials: C
authors.lastname: Tian
authors.forename: Jiyoung
authors.initials: J
authors.lastname: Ahn
authors.forename: Silke
authors.initials: S
authors.lastname: Kropp
authors.forename: Irmgard
authors.initials: I
authors.lastname: Helmbold
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Fournier
authors.forename: Wulf
authors.initials: W
authors.lastname: Haase
authors.forename: Marie Luise
authors.initials: ML
authors.lastname: Sautter-Bihl
authors.forename: Frederik
authors.initials: F
authors.lastname: Wenz
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
mesh_terms: D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000532:radiotherapy / Q000601:surgery; D005260:Female; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics*; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011829:Radiation Dosage; D011855:Radiodermatitis / Q000235:genetics*; D011878:Radiotherapy / Q000009:adverse effects*
chemical_list: C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi