title: Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy.
abstract: The xeroderma pigmentosum group D (XPD) gene encodes a DNA helicase that functions in nucleotide excision repair of chemotherapy-induced DNA damage, the efficiency of which is predicted to be affected by a lysine to glutamine variant at codon 751. We hypothesized that this constitutive genetic variant may modify clinical response to chemotherapy, and we have examined its association with outcome following chemotherapy for acute myeloid leukemia (AML) in 341 elderly patients entered into the United Kingdom Medical Research Council AML 11 trial, and with the risk of developing chemotherapy-related AML. Among subjects treated for AML, disease-free survival at one year was 44% for lysine homozygotes, compared with 36% for heterozygotes and 16% for glutamine homozygotes (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.01-1.70; P = .04). Similarly, overall survival at one year was 38% for lysine homozygotes, 35% for heterozygotes, and 23% for glutamine homozygotes (HR, 1.18; 95% CI, 0.99-1.41; P = .07). Furthermore, homozygosity for the XPD codon 751 glutamine variant was associated with a significantly increased risk of developing AML after chemotherapy (odds ratio, 2.22 for Gln/Gln vs Lys/Lys; 95% CI, 1.04-4.74). These data suggest that the XPD codon 751 glutamine variant protects against myeloid cell death after chemotherapy.
authors.affiliation: Epidemiology and Genetics Unit, Department of Biology, University of York, York, United Kingdom, YO10 5YW. jim.allan@egu.york.ac.uk
authors.forename: James M
authors.initials: JM
authors.lastname: Allan
authors.forename: Alexandra G
authors.initials: AG
authors.lastname: Smith
authors.forename: Keith
authors.initials: K
authors.lastname: Wheatley
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hills
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
authors.forename: Deirdre A
authors.initials: DA
authors.lastname: Hill
authors.forename: David M
authors.initials: DM
authors.lastname: Swirsky
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Morgan
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wild
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D003062:Codon / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D014157:Transcription Factors / Q000235:genetics*; D016896:Treatment Outcome; D051759:Xeroderma Pigmentosum Group D Protein
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D014157:Transcription Factors; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human