Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer.
The authors investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating oxidative stress in sporadic breast cancer. PCR-restriction fragment length polymorphism (RFLP) and PCR-amplified fragment length polymorphism (AFLP) methods were used for genetic analysis in 222 sporadic breast cancer cases and 235 controls. Standardized food frequency questionnaire was used for dietary micronutrient assessment. 8-oxo-2'-deoxyguanosine (8-oxodG), folate, and estradiol were estimated using commercial ELISA kits. Reverse-phase HPLC coupled with fluorescence detector was used for plasma homocysteine analysis. Total glutathione was estimated using Ellman's method. Reduced folate carrier 1 (RFC1) G80A and methylenetetrahydrofolate reductase (MTHFR) C677T were associated with risks of 1.34 (95% CI 1.01-1.79)- and 1.84 (95% CI 1.14-3.00)-folds, respectively, for sporadic breast cancer while cytosolic serine hydroxymethyl transferase (cSHMT) C1420T was associated with reduced risk (OR 0.71, 95% CI 0.53-0.94). Significant increase in plasma 8-oxo-2'-deoxyguanosine (P < 0.004) and homocysteine (P < 0.0001); and significant decrease in total glutathione (P < 0.01) and dietary folate (P = 0.006) was observed in cases than in controls. Oxidative DNA damage showed direct association with menopause (P = 0.02), RFC1 G80A (P < 0.05) and homocysteine (P < 0.0001); and inverse association with dietary folate (P < 0.0001), plasma folate (P < 0.0001), cSHMT C1420T (P < 0.05) and glutathione (P < 0.001). To conclude, the aberrations in one-carbon metabolism induce oxidative stress in sporadic breast cancer either by affecting the folate pool or by impairing remethylation.
Department of Clinical Pharmacology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, India.
Naushad Shaik
NS
Mohammad
Rupasree
R
Yedluri
Pavani
P
Addepalli
Suryanarayana Raju
SR
Gottumukkala
Raghunadha Rao
RR
Digumarti
Vijay Kumar
VK
Kutala
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D004249:DNA Damage; D003839:Deoxyadenosines / Q000097:blood; D004958:Estradiol / Q000097:blood; D005260:Female; D056726:Genetic Association Studies; D005978:Glutathione / Q000097:blood; D006710:Homocysteine / Q000097:blood; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D019875:One-Carbon Group Transferases / Q000235:genetics*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011110:Polymorphism, Genetic; D012307:Risk Factors
D003839:Deoxyadenosines; D026901:Membrane Transport Proteins; C120043:SLC19A2 protein, human; D006710:Homocysteine; D004958:Estradiol; C078251:2'-deoxy-7,8-dihydro-8-oxoadenosine; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D019875:One-Carbon Group Transferases; D005978:Glutathione