Genetic polymorphism of CYP1A1, CYP2D6, GSTM1 and GSTT1 and susceptibility to acute lymphoblastic leukaemia in Indian children.
BACKGROUND
Biotransformation plays a crucial role in carcinogen activity and many genetic polymorphisms in xenobiotic metabolising enzymes have been associated with an increased risk of cancer. Such polymorphisms can lead to considerable variation in the activities of these enzymes, which are crucial in carcinogen and drug metabolism. These variations could play a role in the risk of developing paediatric acute lymphoblastic leukaemia (ALL) by their varying action on environmental carcinogens.


METHODS
The present study looked for two polymorphisms (m1 and m2) in the CYP1A1, CYP2D6*4 genes and deletions of the glutathione S-transferases (GSTM1 and GSTT1) in 118 paediatric ALL patients and 118 age matched control children. The polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) were used to study gene polymorphisms.


RESULTS
In children with ALL, CYP1A1 m1 polymorphism was evident in 42.4% of subjects and CYP1A1 m2 in 37.3%. These were significantly different from the results obtained for control children (20.3% for CYP1A1 m1 and 19.5% for m2). Subjects with CYP1A1 m1 homozygous variant had a sixfold risk and CYP1A1 m2 a fourfold risk. In contrast, CYP2D6*4 was more prevalent in the controls than in the cases. Subjects with GSTM1 deletions had increased risk of ALL (OR = 2.1, P = 0.009). The odds ratios for both CYP1A1 m1 and m2 homozygous polymorphisms being associated with childhood ALL was 5.67 (95% CI = 2.11-15.27). The odds ratios for both GSTM1 and GSTT1 deletions being associated with ALL was 2.78 (95% CI = 0.67-11.56).


CONCLUSIONS
These results suggest that genetic polymorphisms of xenobiotic metabolising enzymes appear to influence susceptibility to childhood ALL.
Joseph
Thomas
T
Department of Molecular Medicine, Drug Development and Chemoinformatics, Regional Cancer Centre, Thiruvananthapuram, India.
Kusumakumary
P
P
Chacko
Priya
P
Abraham
Annie
A
Radhakrishna Pillai
M
M
D000293:Adolescent; D001711:Biotransformation; D002273:Carcinogens / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D007194:India / Q000208:ethnology; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D016017:Odds Ratio; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000208:ethnology / Q000209:etiology / Q000235:genetics*; D015262:Xenobiotics / Q000378:metabolism
D002273:Carcinogens; D019363:Cytochrome P-450 CYP1A1; D019389:Cytochrome P-450 CYP2D6; D005982:Glutathione Transferase; D015262:Xenobiotics; C491107:GSTT2 protein, human; C413545:glutathione S-transferase T1