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Blood, 15 December 2004, Vol. 104, No. 13, pp. 3872-3877.
Prepublished online as a Blood First Edition Paper on August 31, 2004; DOI 10.1182/blood-2004-06-2161.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy
James M. Allan,
Alexandra G. Smith,
Keith Wheatley,
Robert K. Hills,
Lois B. Travis,
Deirdre A. Hill,
David M. Swirsky,
Gareth J. Morgan, and
Christopher P. Wild
From the Epidemiology and Genetics Unit, the Departments of Biology and Health Sciences, University of York, York, United Kingdom; Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, United Kingdom; the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD; the Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds, United Kingdom; the Institute of Cancer Research, Royal Marsden Hospital, Surrey, United Kingdom; and the Molecular Epidemiology Unit, School of Medicine, University of Leeds, Leeds, United Kingdom.
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. (Blood. 2004;104:3872-3877)
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