The Genotype Distribution of the XRCC1, XRCC3, and XPD DNA Repair Genes and Their Role for the Development of Acute Myeloblastic Leukemia Amani Sorour, 1 Mona Wagdy Ayad, 1 and Hala Kassem 2 Aim: To investigate if there is an association between the different DNA repair gene polymorphisms and the risk of development of acute myeloid leukemia (AML) in a sample of the Egyptian population and to find out if there is any interaction between these polymorphisms and the NQO1 gene that acts to protect the cells from oxidative damage. Results: Our study was conducted on 90 patients with de novo AML and 60 healthy subjects with matched age and sex. We studied polymorphisms in three DNA repair genes; XRCC1, XRCC3, and XPD. We also assessed the incidence of the NQO1 gene polymorphism. We genotyped the polymorphisms by polymerase chain reaction– restriction fragment length polymorphism. Conclusion: The distribution of XRCC1Arg 339Gln genotypes showed a significant difference between patients and controls ( p = 0.025). The presence of at least one XRCC1 399Gln allele indicated an increased risk of AML and the proportion of AML patients homozygous for the Gln/Gln allele was significantly higher than in the control group ( p = 0.025). However, distributions of the XRCC3 Thr241Met, XPD Lys751Gln, and NQO1Pro 187Ser genotypes were not significantly different between patients and controls. Combined analysis of the studied DNA repair gene polymorphisms did not show an interaction with the detoxification NQO1 Pro187Ser polymorphism. Introduction A cute myeloid leukemia (AML) is a clonal disorder characterized by acquisition of somatic mutations in hematopoietic progenitors leading to disruption of differen- tiation. Most cases of AML are de novo, with no known exposure to leukemogenic substances. However, about 10%– 20% of all cases of AML arise after chemotherapy used to treat other malignant diseases (therapy-related AML [t-AML]) (Pedersen-Bjergaard et al., 2002). Many genes encode proteins that function to protect cells against genetic instability by means of different mechanisms, mainly DNA repair pathways and protection against oxida- tive stress (Loeb, 1991). DNA repair pathways play a vital role in maintaining ge- netic integrity, and it is becoming clear that defects in repair pathways are connected to many different types of diseases, including leukemia and cancer (Loeb, 1991). Protection against oxidative damage functions through genes, such as nicotinamide adenine dinucleotide phosphate oxidoreductase (NQO1); its polymorphism NQO1 Pro187Ser has been reported to predispose to AML (Dinkova-Kostova and Talalay, 2010). At least four pathways of DNA repair operate on different types of damaged DNA. Base excision repair (BER) operates on small lesions, while the nucleotide excision repair (NER) pathway repairs bulk lesions. Mismatch repair (MMR) cor- rects replication errors. Double-strand DNA break repair (DSBR) consists of two pathways, homologous recombination (HR) and nonhomologous end joining (NHEJ). The NHEJ repair pathway involves direct ligation of the two double- strand break ends. In HR, the double-strand DNA breaks are repaired through alignment of homologous sequences of DNA (Hoeijmakers, 2001). Polymorphisms in DNA repair genes may affect the DNA repair capacity and modulate cancer susceptibility by means of gene–environment interactions. XRCC1, XRCC3, and XPD are polymorphic genes belonging to three of the major DNA repair genes pathways. The XRCC1 gene codes for a protein involved in the repair of asingle-strand repair and BER of damaged bases caused by endogenous and exogenous damaging agents (Seedhouse, et al., 2002). Three polymorphisms occurring at the conserved se- quences in the XRCC1 gene were reported. These coding polymorphisms resulting in amino acid substitution were 1 Department of Clinical Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt. 2 Institute of Medical Research, Alexandria University, Alexandria, Egypt. GENETIC TESTING AND MOLECULAR BIOMARKERS Volume 17, Number 3, 2013 ª Mary Ann Liebert, Inc. Pp. 195–201 DOI: 10.1089/gtmb.2012.0278 195