title: Association of DNA repair and steroid metabolism gene polymorphisms with clinical late toxicity in patients treated with conformal radiotherapy for prostate cancer.
abstract: OBJECTIVE
  To explore the possible relationship between single nucleotide polymorphisms (SNP) in candidate genes encoding DNA damage recognition/repair/response and steroid metabolism proteins with respect to clinical radiation toxicity in a retrospective cohort of patients previously treated with three-dimensional conformal radiotherapy (3-DCRT) for prostate cancer.
  
  
  METHODS
  One hundred twenty-four patients with prostate cancer underwent 3-DCRT at our institution between September 1996 and December 2000. Of these, 83 consented for follow-up of blood sampling and SNP analysis. Twenty-eight patients were documented as having experienced grade >/=2 late bladder or rectal toxicity (scoring system of Radiation Therapy Oncology Group) on at least one follow-up visit. We analyzed 49 SNPs in BRCA1, BRCA2, ESR1, XRCC1, XRCC2, XRCC3, NBN, RAD51, RAD52, LIG4, ATM, BCL2, TGFB1, MSH6, ERCC2, XPF, NR3C1, CYP1A1, CYP2C9, CYP2C19, CYP3A5, CYP2D6, CYP11B2, and CYP17A1 genes using the Pyrosequencing technique.
  
  
  RESULTS
  Significant univariate associations with late rectal or bladder toxicity (grade >/=2) were found for XRCC3 (A>G 5' untranslated region NT 4541), LIG4 (T>C Asp(568)Asp), MLH1 (C>T, Val(219)Ile), CYP2D6*4 (G>A splicing defect), mean rectal and bladder dose, dose to 30% of rectum or bladder, and age <60 years. On Cox multivariate analysis, significant associations with toxicity were found for LIG4 (T>C, Asp(568)Asp), ERCC2 (G>A, Asp(711)Asp), CYP2D6*4 (G>A, splicing defect), mean bladder dose >60 Gy, and dose to 30% of rectal volume >75 Gy.
  
  
  CONCLUSIONS
  In this study, we identified SNPs in LIG4, ERCC2, and CYP2D6 genes as putative markers to predict individuals at risk for complications arising from radiation therapy in prostate cancer.
authors.affiliation: Cross Cancer Institute, Department of Oncology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Sambasivarao
authors.initials: S
authors.lastname: Damaraju
authors.forename: David
authors.initials: D
authors.lastname: Murray
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dufour
authors.forename: Diana
authors.initials: D
authors.lastname: Carandang
authors.forename: Sten
authors.initials: S
authors.lastname: Myrehaug
authors.forename: Gino
authors.initials: G
authors.lastname: Fallone
authors.forename: Colin
authors.initials: C
authors.lastname: Field
authors.forename: Russell
authors.initials: R
authors.lastname: Greiner
authors.forename: John
authors.initials: J
authors.lastname: Hanson
authors.forename: Carol E
authors.initials: CE
authors.lastname: Cass
authors.forename: Matthew
authors.initials: M
authors.lastname: Parliament
mesh_terms: D000368:Aged; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics; D015331:Cohort Studies; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000235:genetics; D004260:DNA Repair / Q000235:genetics* / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000235:genetics; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*; D011879:Radiotherapy Dosage; D020266:Radiotherapy, Conformal / Q000009:adverse effects / Q000379:methods*; D012007:Rectum / Q000473:pathology / Q000528:radiation effects; D012189:Retrospective Studies; D013256:Steroids / Q000378:metabolism*; D001743:Urinary Bladder / Q000473:pathology / Q000528:radiation effects; D051759:Xeroderma Pigmentosum Group D Protein / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; D024682:BRCA2 Protein; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C000607893:LIG4 protein, human; D013256:Steroids; D003577:Cytochrome P-450 Enzyme System; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP