Polymorphisms in human homeobox HLX1 and DNA repair RAD51 genes increase the risk of therapy-related acute myeloid leukemia.
Studies of radiation-induced acute myeloid leukemia (AML) in mice suggest that the number of target stem cells is a risk factor, and the HLX1 homeobox gene, which is important for hematopoietic development, is a candidate gene. The distribution of the C/T-3' untranslated region (UTR) polymorphism in HLX1 in patients with AML and therapy-related AML (t-AML) compared with controls was therefore determined. The presence of the variant HLX1 allele significantly increases the risk of t-AML (OR = 3.36, 95% CI, 1.65-6.84). The DNA repair gene RAD51 (135G/C-5' UTR) polymorphism also increases t-AML risk, and when combined analysis was performed on both RAD51 and HLX1 variant alleles, a synergistic 9.5-fold increase (95% CI, 2.22-40.64) in the risk of t-AML was observed. We suggest that the HLX1 polymorphism has an effect on stem cell numbers, whereas an increased DNA repair capacity (RAD51) will suppress apoptosis, a genetic interaction that may increase the number of genomes at risk during cancer therapy.
Jawad
Mays
M
Department of Academic Haematology, Clinical Sciences Building, Nottingham University Hospitals, Nottingham NG5 1PB, United Kingdom.
Seedhouse
Claire Helen
CH
Russell
Nigel
N
Plumb
Mark
M
D020121:5' Untranslated Regions / Q000235:genetics; D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D016609:Neoplasms, Second Primary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020641:Polymorphism, Single Nucleotide; D051135:Rad51 Recombinase / Q000235:genetics* / Q000378:metabolism; D012307:Risk Factors; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D020121:5' Untranslated Regions; C084058:HLX protein, human; D018398:Homeodomain Proteins; D009363:Neoplasm Proteins; D014157:Transcription Factors; C495153:RAD51 protein, human; D051135:Rad51 Recombinase