Advertisement

Molecular Biology Reports

, Volume 38, Issue 8, pp 4893–4901 | Cite as

Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer

  • Shaik Mohammad Naushad
  • Addepalli Pavani
  • Raghunadha Rao Digumarti
  • Suryanarayana Raju Gottumukkala
  • Vijay Kumar Kutala
Article

Abstract

In view of growing body of evidence substantiating the role of aberrations in one-carbon metabolism in the pathophysiology of breast cancer and lack of studies on gene–gene interactions, we investigated the role of dietary micronutrients and eight functional polymorphisms of one-carbon metabolism in modulating the breast cancer risk in 244 case–control pairs of Indian women and explored possible gene–gene interactions using Multifactor dimensionality reduction analysis (MDR). Dietary micronutrient status was assessed using the validated Food Frequency Questionnaire. Genotyping was done for glutamate carboxypeptidase II (GCPII) C1561T, reduced folate carrier (RFC)1 G80A, cytosolic serine hydroxymethyltransferase (cSHMT) C1420T, thymidylate synthase (TYMS) 5′-UTR tandem repeat, TYMS 3′-UTR ins6/del6, methylenetetrahydrofolate reductase (MTHFR) C677T, methyltetrahydrofolate-homocysteine methyltransferase (MTR) A2756G, methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) A66G polymorphisms by using the PCR-RFLP/AFLP methods. Low dietary folate intake (P < 0.001), RFC1 G80A (OR: 1.38, 95% CI 1.06–1.81) and MTHFR C677T (OR: 1.74 (1.11–2.73) were independently associated with the breast cancer risk whereas cSHMT C1420T conferred protection (OR: 0.72, 95% CI 0.55–0.94). MDR analysis demonstrated a significant tri-variate interaction among RFC1 80, MTHFR 677 and TYMS 5′-UTR loci (P trend < 0.02) with high-risk genotype combination showing inflated risk for breast cancer (OR 4.65, 95% CI 1.77–12.24). To conclude, dietary as well as genetic factors were found to influence susceptibility to breast cancer. Further, the current study highlighted the importance of multi-loci analyses over the single-locus analysis towards establishing the epistatic interactions between loci of one-carbon metabolism modulate susceptibility to the breast cancer.

Keywords

Breast cancer One-carbon metabolism Dietary micronutrients Epistasis Multifactor dimensionality reduction 

Notes

Acknowledgments

This work was supported by the grant funded by Indian Council of Medical Research (ICMR), New Delhi (Ref No. 5/13/32/2007). We thank Miss Y. Rupasree, Mrs. S.V. Vijaya Lakshmi, Miss P. Shree Divyya and Mr. E. Chandra Sekhar for providing technical support.

References

  1. 1.
    Murthy NS, Chaudhry K, Nadayil D, Agarwal UK, Saxena S (2009) Changing trends in incidence of breast cancer: Indian scenario. Indian J Cancer 46:73–74PubMedCrossRefGoogle Scholar
  2. 2.
    Rebbeck TR, Walker AH, Phelan CM, Godwin AK, Buetow KH, Garber JE, Narod SA, Weber BL (1997) Defining etiologic heterogeneity in breast cancer using genetic biomarkers. Prog Clin Biol Res 396:53–61 ReviewPubMedGoogle Scholar
  3. 3.
    Halapi E, Hakonarson H (2002) Advances in the development of genetic markers for the diagnosis of disease and drug response. Expert Rev Mol Diagn 2(5):411–421 ReviewPubMedCrossRefGoogle Scholar
  4. 4.
    Ford D, Easton DF (1995) The genetics of breast and ovarian cancer. Br J Cancer 72:805–812PubMedCrossRefGoogle Scholar
  5. 5.
    Melnyk S, Pogribna M, Miller BJ, Basnakian AG, Pogribny IP, James SJ (1999) Uracil misincorporation, DNA strand breaks, and gene amplification are associated with tumorigenic cell transformation in folate deficient/repleted Chinese hamster ovary cells. Cancer Lett 146(1):35–44PubMedCrossRefGoogle Scholar
  6. 6.
    Christman JK, Sheikhnejad G, Dizik M, Abileah S, Wainfan E (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe dietary methyl deficiency. Carcinogenesis 14(4):551–557PubMedCrossRefGoogle Scholar
  7. 7.
    Lee SA, Kang D, Nishio H, Lee MJ, Kim DH, Han W, Yoo KY, Ahn SH, Choe KJ, Hirvonen A, Noh DY (2004) Methylenetetrahydrofolate reductase polymorphism, diet, and breast cancer in Korean women. Exp Mol Med 36(2):116–121PubMedGoogle Scholar
  8. 8.
    Xu X, Gammon MD, Zhang H, Wetmur JG, Rao M, Teitelbaum SL, Britton JA, Neugut AI, Santella RM, Chen J (2007) Polymorphisms of one-carbon-metabolizing genes and risk of breast cancer in a population-based study. Carcinogenesis 28(7):1504–1509PubMedCrossRefGoogle Scholar
  9. 9.
    Cheng CW, Yu JC, Huang CS, Shieh JC, Fu YP, Wang HW, Wu PE, Shen CY (2008) Polymorphism of cytosolic serine hydroxymethyltransferase, estrogen and breast cancer risk among Chinese women in Taiwan. Breast Cancer Res Treat 111(1):145–155PubMedCrossRefGoogle Scholar
  10. 10.
    Akisik E, Dalay N (2007) Functional polymorphism of thymidylate synthase, but not of the COMT and IL-1B genes, is associated with breast cancer. J Clin Lab Anal 21(2):97–102PubMedCrossRefGoogle Scholar
  11. 11.
    Chen J, Gammon MD, Chan W, Palomeque C, Wetmur JG, Kabat GC, Teitelbaum SL, Britton JA, Terry MB, Neugut AI, Santella RM (2005) One-carbon metabolism, MTHFR polymorphisms, and risk of breast cancer. Cancer Res 65(4):1606–1614PubMedCrossRefGoogle Scholar
  12. 12.
    Grieu F, Powell B, Beilby J, Iacopetta B (2004) Methylenetetrahydrofolate reductase and thymidylate synthase polymorphisms are not associated with breast cancer risk or phenotype. Anticancer Res 24(5B):3215–3219PubMedGoogle Scholar
  13. 13.
    Lissowska J, Gaudet MM, Brinton LA, Chanock SJ, Peplonska B, Welch R, Zatonski W, Szeszenia-Dabrowska N, Park S, Sherman M, Garcia-Closas M (2007) Genetic polymorphisms in the one-carbon metabolism pathway and breast cancer risk: a population-based case-control study and meta-analyses. Int J Cancer 120(12):2696–2703PubMedCrossRefGoogle Scholar
  14. 14.
    Pepe C, Guidugli L, Sensi E, Aretini P, D’Andrea E, Montagna M, Manoukian S, Ottini L, Radice P, Viel A, Bevilacqua G, Caligo MA (2007) Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers. Breast Cancer Res Treat 103(1):29–36PubMedCrossRefGoogle Scholar
  15. 15.
    Lin WY, Chou YC, Wu MH, Huang HB, Jeng YL, Wu CC, Yu CP, Yu JC, You SL, Chu TY, Chen CJ, Sun CA (2004) The MTHFR C677T polymorphism, estrogen exposure and breast cancer risk: a nested case-control study in Taiwan. Anticancer Res 24(6):3863–3868PubMedGoogle Scholar
  16. 16.
    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Jin F, Zheng W (2006) MTR and MTRR polymorphisms, dietary intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 15(3):586–588PubMedCrossRefGoogle Scholar
  17. 17.
    Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Brüning T, Ko Y, Brauch H (2005) One-carbon metabolism and breast cancer risk: no association of MTHFR, MTR, and TYMS polymorphisms in the GENICA study from Germany. Cancer Epidemiol Biomarkers Prev 14(12):3015–3018PubMedCrossRefGoogle Scholar
  18. 18.
    Matsuo K, Hamajima N, Hirai T, Kato T, Inoue M, Takezaki T, Tajima K (2002) Methionine synthase reductase gene A66G polymorphism is associated with risk of colorectal cancer. Asian Pac J Cancer Prev 3(4):353–359PubMedGoogle Scholar
  19. 19.
    Gemmati D, Ongaro A, Scapoli GL, Della Porta M, Tognazzo S, Serino ML, Di Bona E, Rodeghiero F, Gilli G, Reverberi R, Caruso A, Pasello M, Pellati A, De Mattei M (2004) Common gene polymorphisms in the metabolic folate and methylation pathway and the risk of acute lymphoblastic leukemia and non-Hodgkin’s lymphoma in adults. Cancer Epidemiol Biomarkers Prev 13(5):787–794PubMedGoogle Scholar
  20. 20.
    Shi Q, Zhang Z, Li G, Pillow PC, Hernandez LM, Spitz MR, Wei Q (2005) Polymorphisms of methionine synthase and methionine synthase reductase and risk of lung cancer: a case-control analysis. Pharmacogenet Genomics 15(8):547–555PubMedCrossRefGoogle Scholar
  21. 21.
    Zhang Z, Shi Q, Liu Z, Sturgis EM, Spitz MR, Wei Q (2005) Polymorphisms of methionine synthase and methionine synthase reductase and risk of squamous cell carcinoma of the head and neck: a case-control analysis. Cancer Epidemiol Biomarkers Prev 14(5):1188–1193PubMedCrossRefGoogle Scholar
  22. 22.
    Carr DF, Whiteley G, Alfirevic A, Pirmohamed M, FolATED study team (2009) Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review. Pharmacogenomics J 9(5):291–305 ReviewPubMedCrossRefGoogle Scholar
  23. 23.
    Kumar K, Kaiser J (2006) Methylene tetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms and breast cancer in South Indian population. Int J Cancer Res 2(2):143–151CrossRefGoogle Scholar
  24. 24.
    Gopalan C, Rama Sastri BV, Balasubramanian SC (2007) Nutritive value of Indian foods. National Institute of Nutrition, Indian Council of Medical Research, IndiaGoogle Scholar
  25. 25.
    Krebs J (2002) McCance and Widdowson’s the composition of foods: summary edition, 6th summary ed. The Royal Society of Chemistry/Food Standards Agency, Cambridge/LondonGoogle Scholar
  26. 26.
    U.S. Department of Agriculture, Agricultural Research Service (2006) USDA National Nutrient Database for Standard Reference, Release 18. Nutrient Data Laboratory Home Page. http://www.ars.usda.gov/ba/bhnrc/ndl
  27. 27.
    Salazar LA, Hirata MH, Cavalli SA, Machado MO, Hirata RD (1998) Optimized procedure for DNA isolation from fresh and cryopreserved clotted human blood useful in clinical molecular testing. Clin Chem 44:1748–1750PubMedGoogle Scholar
  28. 28.
    Pike MC, Spicer DV, Dahmoush L, Press MF (1993) Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 15(1):17–35PubMedGoogle Scholar
  29. 29.
    Ursin G, London S, Stanczyk FZ, Gentzschein E, Paganini-Hill A, Ross RK, Pike MC (1999) Urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 91(12):1067–1072PubMedCrossRefGoogle Scholar
  30. 30.
    Jansen G, Mauritz R, Drori S, Sprecher H, Kathmann I, Bunni M, Priest DG, Noordhuis P, Schornagel JH, Pinedo HM, Peters GJ, Assaraf YG (1998) A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. J Biol Chem 273(46):30189–30198PubMedCrossRefGoogle Scholar
  31. 31.
    Chango A, Emery-Fillon N, de Courcy GP, Lambert D, Pfister M, Rosenblatt DS, Nicolas JP (2000) A polymorphism (80 G → A) in the reduced folate carrier gene and its associations with folate status and hyperhomocysteinemia. Mol Genet Metab 70:310–315PubMedCrossRefGoogle Scholar
  32. 32.
    Ifergan I, Jansen G, Assaraf YG (2008) The reduced folate carrier (RFC) is cytotoxic to cells under conditions of severe folate deprivation. RFC as a double edged sword in folate homeostasis. J Biol Chem 283(30):20687–20695PubMedCrossRefGoogle Scholar
  33. 33.
    Yamada K, Chen Z, Rozen R, Matthews RG (2001) Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase. Proc Natl Acad Sci USA 98(26):14853–14858PubMedCrossRefGoogle Scholar
  34. 34.
    Sharp L, Little J, Schofield AC, Pavlidou E, Cotton SC, Miedzybrodzka Z, Baird JO, Haites NE, Heys SD, Grubb DA (2002) Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett 181(1):65–71PubMedCrossRefGoogle Scholar
  35. 35.
    Shrubsole MJ, Gao YT, Cai Q, Shu XO, Dai Q, Hébert JR, Jin F, Zheng W (2004) MTHFR polymorphisms, dietary folate intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Epidemiol Biomarkers Prev 13(2):190–196PubMedCrossRefGoogle Scholar
  36. 36.
    Beilby J, Ingram D, Hähnel R, Rossi E (2004) Reduced breast cancer risk with increasing serum folate in a case-control study of the C677T genotype of the methylenetetrahydrofolate reductase gene. Eur J Cancer 40(8):1250–1254PubMedCrossRefGoogle Scholar
  37. 37.
    Campbell IG, Baxter SW, Eccles DM, Choong DY (2002) Methylenetetrahydrofolate reductase polymorphism and susceptibility to breast cancer. Breast Cancer Res 4(6):R14PubMedCrossRefGoogle Scholar
  38. 38.
    Horie N, Aiba H, Oguro K, Hojo H, Takeishi K (1995) Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5′-terminal regulatory region of the human gene for thymidylate synthase. Cell Structr Funct 20(3):191–197CrossRefGoogle Scholar
  39. 39.
    Heil SG, Van der Put NM, Wass ET, den Heijer M, Trijbels FJ, Blom HJ (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 73(2):164–172PubMedCrossRefGoogle Scholar
  40. 40.
    Fu TF, Hunt S, Schirch V, Safo MK, Chen BH (2005) Properties of human and rabbit cytosolic serine hydroxymethyltransferase are changed by single nucleotide polymorphic mutations. Arch Biochem Biophys 442(1):92–101PubMedCrossRefGoogle Scholar
  41. 41.
    Reed MC, Nijhout HF, Neuhouser ML, Gregory JF III, Shane B, James SJ, Boynton A, Ulrich CM (2006) A mathematical model gives insights into nutritional and genetic aspects of folate-mediated one-carbon metabolism. J Nutr 136(10):2653–2661PubMedGoogle Scholar
  42. 42.
    Dizik M, Christman JK, Wainfan E (1991) Alterations in expression and methylation of specific genes in livers of rats fed a cancer promoting methyl-deficient diet. Carcinogenesis 12(7):1307–1312PubMedCrossRefGoogle Scholar
  43. 43.
    Butterworth M, Lau SS, Monks TJ (1996) 17 beta-Estradiol metabolism by hamster hepatic microsomes. Implications for the catechol-O-methyl transferase-mediated detoxication of catechol estrogens. Drug Metab Dispos 24(5):588–594PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Shaik Mohammad Naushad
    • 1
  • Addepalli Pavani
    • 1
  • Raghunadha Rao Digumarti
    • 2
  • Suryanarayana Raju Gottumukkala
    • 3
  • Vijay Kumar Kutala
    • 1
  1. 1.Department of Clinical Pharmacology & TherapeuticsNizam’s Institute of Medical SciencesHyderabadIndia
  2. 2.Department of Medical OncologyNizam’s Institute of Medical SciencesHyderabadIndia
  3. 3.Department of Surgical OncologyNizam’s Institute of Medical SciencesHyderabadIndia

Personalised recommendations