Genetic variation in XPD predicts treatment outcome and risk of acute myeloid leukemia following chemotherapy
2004
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
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