Asian Pacific Journal of Cancer Prevention

Asian Pacific Journal of Cancer Prevention (아시아태평양암예방학회)
권호 표지
DOI QR코드

DOI QR Code

Mutational Analysis of the MTHFR Gene in Breast Cancer Patients of Pakistani Population

  • Akram, Muhammad (Department of Biosciences, COMSTS Institute of Information Technology) ;
  • Malik, Fa (Department of Biosciences, COMSTS Institute of Information Technology) ;
  • Kayani, Mahmood Akhtar (Department of Biosciences, COMSTS Institute of Information Technology)
  • Published : 2012.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Objectives: Since methylenetetrahydrofolate reductase (MTHFR) maintains the balance of circulating folate and methionine and blocks the formation of homocysteine, its regulation in relation to different cancers has extensively been studied in different populations. However, information on Pakistani breast cancer patients is lacking. The MTHFR gene has two most common mutations that are single nucleotide additions which result in change of amino acids C677T to Ala222val and A1298C to Glu429Ala. Methodology: 110 sporadic breast patients with no prior family history of cancer or any other type of genetic disorders along with 110 normal individuals were screened for mutations in exons 1 to exon 9 using single strand conformational polymorphism, RFLP and sequencing analyzer. Results: The p values for the 677CC, 677CT, and 677TT genotypes were 0.223, 0.006, and 0.077, respectively. Those for the 1298AA, 1298AC, and 1298CC genotypes were 0.555, 0.009, and 0.003, respectively. Conclusions: We found an overall a significant, weak inverse association between breast cancer risk and the 677TT genotype and an inverse association with the 1298C variant. These results for MTHFR polymorphism might be population specific in sporadic breast cancer affected patients but many other factors need to be excluded before making final conclusions including folate intake, population and disease heterogeneity.

Keywords

References

  1. Ames BN (1999). Cancer prevention and diet: help from single nucleotide polymorphisms. Proc Natl Acad Sci USA, 96, 12216-8. https://doi.org/10.1073/pnas.96.22.12216
  2. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997). Folate deficiency causs uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci USA, 94, 3290-5. https://doi.org/10.1073/pnas.94.7.3290
  3. Feigelson HS, Jonas CR, Robertson AS, et al (2003). Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev, 12, 161-4.
  4. Ford ES, Bowman BA (1999). Serum and red blood cells folate concentrations, race and education: Finding from the third National Health and nutrition survey. Am J Clin Ntr, 134, 1786-92.
  5. Frosst P (1995). A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase. Nat Genet, 10, 111-3. https://doi.org/10.1038/ng0595-111
  6. Gaugham DJ, Barbaux S, Kluijtmans LA, Whitehead AS (2000). The human and mouse methylenetetrahydrofolate reductase (MTHFR) genes: genomic organization, mRNA structure and linkage to the CLCN6 gene. Gene, 257, 279-89. https://doi.org/10.1016/S0378-1119(00)00392-9
  7. Gershoni-Baruch R, Dagan E, Israeli D, et al (2000). Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women. Eur Cancer, 36, 2313-6. https://doi.org/10.1016/S0959-8049(00)00306-3
  8. Goyette P, Pai A, Milos R, et al (1999). Gene structure of human and mouse methylenetetrahydrofolate reductase (MTHFR). Mamm Genome, 9, 652-6.
  9. Heniquez-Hernandez LA, Perez LF, Hernandez AG, et al (2010). TYMS, MTHFR, p53 and MDR1 gene polymorphisms in breast cancer patients treated with adjuvant therapy. Cancer Epidemiol, 34, 490-3. https://doi.org/10.1016/j.canep.2010.03.004
  10. Heniquez-Hernandez LA, Murias-Rosales A, Hernandez Gonzalez A, et al (2009). Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: A case-control study. Oncology Reports, 22, 1425-33.
  11. Helms C (1990). Salting out Procedure for Human DNA extraction. In The Donis-Keller Lab - Lab Manual Homepage.
  12. Justenhoven C, Hamann U, Pierl CB, et al (2005). One-corbon metabolism in breast cancer risk in colon and no association of MTHFR, MTR and TYMS polymorphism in the GENICA study from the Germany. Cancer Epidemiol Biomarkers Prev, 14, 1315-8. https://doi.org/10.1158/1055-9965.EPI-05-0032
  13. Jencks DA, Mathews RG (1987). Allosteric inhibition of methylenetetrahydrofolate reductase by adenosylmethionine. J Biol Chem, 262, 2485-93.
  14. Kotsopoulos J, Zhang WW, Zhang S, et al (2008). Polymorphism in folate metabolizing enzymes and transport proteins and risk of breast cancer. Breast Can Res Treat, 112, 585-93. https://doi.org/10.1007/s10549-008-9895-6
  15. Kim YI (2000). Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev, 58, 205-9.
  16. Kim YI (1999). Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem, 10, 66-88. https://doi.org/10.1016/S0955-2863(98)00074-6
  17. Kang SS, Zhou J, Wong PW (1988). Intermediate homocysteinemia: A thermolabile variant of methylenetetrahydrofolate reductase. Am J Hum Genet, 43, 414-21.
  18. Lee SA, Kang D, Nishio H, et al(2004). Methylenetetrahydrofolate reductase polymorphism, diet and breast cancer in Korean women. Exp Mol Med, 36, 116-21. https://doi.org/10.1038/emm.2004.17
  19. Langsenlehner U, Krippl P, Renner W, et al(2003). The common 677C>T gene polymorphism of methylenetetrahydrofolate reductase gene is not associated with breast cancer risk. Breast Cancer Res Treat, 81, 169-72. https://doi.org/10.1023/A:1025752420309
  20. Mushahida Batool, Mustafa Arian, Javaid Gardezi (2005). An experience with breast disease in a surgical unit of a teaching hospital of Lahore. Biomedica, 21, 16.
  21. Marchand L (2004). MTHFR polymorphisms, diet, HRT, and breast cancer risk: the multiethnic cohort study. Cancer Epidemiol Biomarkers Prev, 13, 2071-7.
  22. Molloy AM, Daly S, Mills JL, et al (1997). Thermolabile variant of 5, 10-Methylenetetrahydrofolate reductase associated with low red-cell folate: implications for folate intake recommendations. Lancet, 349, 1591-3. https://doi.org/10.1016/S0140-6736(96)12049-3
  23. Mason JB, Levesque T(1996). Folate effects on carcinogenesis and potential for cancer chemoprevention. Oncology, 10, 1727-36.
  24. Ma t thews RG, Daubne r SC (1982) . Modulation of methylenetetrahydrofolate reductase activity by S-adenosylmethionine and by dihydrofolate and its polyglutamate analogues. Adv Enzyme Regul, 20, 123-31. https://doi.org/10.1016/0065-2571(82)90012-7
  25. Mudd SH, Uhlendorf BW, Freeman JM (1972). Homocystinuria associated with decreased methylenetetrahydrofolate reductase activity. Biochem Biophys Res Commun, 46, 905-12. https://doi.org/10.1016/S0006-291X(72)80227-4
  26. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T (1989). Detection of polymorphism of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc Natl Acad Sci USA, 86, 2766-70. https://doi.org/10.1073/pnas.86.8.2766
  27. Perry CA, Renna SA, Khitun E, et al (2004). Ethnicity and race influence the folate status response to controlled folate intakes in young women. J Nutr, 134, 1786-92.
  28. Rady PL (2002). Genetic polymorphisms of methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) in ethnic populations in Texas; a report of a novel MTHFR polymorphic site, G1793A. Am J Med Genet, 107, 162-8. https://doi.org/10.1002/ajmg.10122
  29. Rohan TE, Jain MG, Howe GR, Miller AB (2000). Dietary folate consumption and breast cancer risk. J Natl Cancer Inst, 92, 266-9. https://doi.org/10.1093/jnci/92.3.266
  30. Rozen R (1997). Genetic predisposition to hyperhomocysteinemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost, 78, 523-6.
  31. Rosenblatt DS (1995). Inherited disorders of folate transport and metabolism. In: Scriver CR, Beaud et al., Sly WS. The metabolic and molecular bases of inherited disease. New York, NY, McGraw-Hill Book Company, 3111-28.
  32. Sharp L (2002). Folate and breast cancer: the role of polymorphisms in methylenetetrahydrofolate reductase (MTHFR). Cancer Lett, 181, 65-71. https://doi.org/10.1016/S0304-3835(02)00030-7
  33. Sellers TA, Kushi LH, Cerhan JR, et al (2001). Dietary folate intake, alcohol, and risk of breast cancer in a prospective study of postmenopausal women. Epidemiology, 12, 420-8. https://doi.org/10.1097/00001648-200107000-00012
  34. Shrubsole MJ, Jin F, Dai Q, et al (2001). Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res, 61, 7136-41.
  35. Tran P, Leclerc D, Chan M (2002). Multiple transcription start sites and alternative splicing in the methylenetetrahydrofolate reductase gene result in two enzyme isoforms. Mamm Genome, 13, 483-92. https://doi.org/10.1007/s00335-002-2167-6
  36. Walsh T, Casadei S, Coats KH, et al (2006). Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA, 295,1379-88. https://doi.org/10.1001/jama.295.12.1379
  37. Weisberg I (1998). A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab, 64, 169-72 https://doi.org/10.1006/mgme.1998.2714
  38. Zang S, Hunter DJ, Hankinson SE, et al (1999). A prospective study of folate intake and risk of breast cancer. JAMA, 281, 1632-7. https://doi.org/10.1001/jama.281.17.1632

Cited by

  1. Germ-line MTHFR C677T, FV H1299R and PAI-1 5G/4G Variations in Breast Carcinoma vol.14, pp.5, 2013, https://doi.org/10.7314/APJCP.2013.14.5.2903
  2. Lack of association between MHTFR Glu429Ala polymorphism and breast cancer susceptibility: a systematic review and meta-analysis of 29 research studies vol.34, pp.2, 2013, https://doi.org/10.1007/s13277-013-0665-7
  3. The Methylenetetrahydrofolate Reductase C677T Polymorphism and Breast Cancer Risk in Asian Populations vol.15, pp.14, 2014, https://doi.org/10.7314/APJCP.2014.15.14.5853
  4. Association of methylenetetrahydrofolate reductase and methionine synthase polymorphisms with breast cancer risk and interaction with folate, vitamin B6, and vitamin B12 intakes vol.35, pp.12, 2014, https://doi.org/10.1007/s13277-014-2456-1
  5. A meta-analysis of genotypes and haplotypes of methylenetetrahydrofolate reductase gene polymorphisms in breast cancer vol.41, pp.9, 2014, https://doi.org/10.1007/s11033-014-3450-9
  6. Association of 677 C>T (rs1801133) and 1298 A>C (rs1801131) Polymorphisms in the MTHFR Gene and Breast Cancer Susceptibility: A Meta-Analysis Based on 57 Individual Studies vol.9, pp.6, 2014, https://doi.org/10.1371/journal.pone.0071290
  7. MTHFR 677C>T Polymorphism and the Risk of Breast Cancer: Evidence from an Original Study and Pooled Data for 28031 Cases and 31880 Controls vol.10, pp.3, 2015, https://doi.org/10.1371/journal.pone.0120654
  8. Association between MTHFR gene 1298A>C polymorphism and breast cancer susceptibility: a meta-analysis based on 38 case-control studies with 40,985 subjects vol.14, pp.1, 2016, https://doi.org/10.1186/s12957-016-0978-2
  9. Association between the MTHFR C677T Polymorphism and Breast Cancer Risk: A Meta-Analysis of 23 Case-Control Studies vol.22, pp.5, 2016, https://doi.org/10.1111/tbj.12639
  10. Population-level diversity in the association of genetic polymorphisms of one-carbon metabolism with breast cancer risk vol.7, pp.4, 2016, https://doi.org/10.1007/s12687-016-0277-1
  11. Association of MHTFR Ala222Val (rs1801133) polymorphism and breast cancer susceptibility: An update meta-analysis based on 51 research studies vol.7, pp.1, 2012, https://doi.org/10.1186/1746-1596-7-171