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Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer

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Abstract

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.

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Abbreviations

8-oxodG:

8-Oxo-2′-deoxyguanosine

AFLP:

Amplified fragment length polymorphism

E2:

Estradiol

GCPII:

Glutamate carboxypeptidase II

MTR:

Methionine synthase

MTRR:

Methionine synthase reductase

MTHF:

Methylene tetrahydrofolate

MTHFR:

Methylenetetrahydrofolate reductase

PCR:

Polymerase chain reaction

RFC1:

Reduced folate carrier 1

RFLP:

Restriction fragment length polymorphism

cSHMT:

Cytosolic serine hydroxymethyltransferase

tHcy:

Total plasma Homocysteine

THF:

Tetrahydrofolate

TYMS:

Thymidylate synthase

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Acknowledgment

This study was supported by the grant funded by Indian Council of Medical Research (ICMR), New Delhi (Ref No. 5/13/32/2007).

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Correspondence to Vijay Kumar Kutala.

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Mohammad, N.S., Yedluri, R., Addepalli, P. et al. Aberrations in one-carbon metabolism induce oxidative DNA damage in sporadic breast cancer. Mol Cell Biochem 349, 159–167 (2011). https://doi.org/10.1007/s11010-010-0670-8

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