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The association between two polymorphisms in the TYMS gene and breast cancer risk: a meta-analysis

  • Epidemiology
  • Published:
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Abstract

Thymidylate synthase (TYMS), which catalyzes the conversion of deoxyuridine monophosphate to deoxythymidine monophosphate, is a central enzyme in the folate metabolic pathway. Epidemiological studies have evaluated the association between TYMS gene polymorphisms and breast cancer susceptibility; however, the published data are still inconclusive. To derive a more precise assessment of this relationship, we performed a meta-analysis based on currently available data by searching PubMed, EMBASE databases, and the Cochrane Library. A total of 10 eligible studies were identified for the TYMS TSER polymorphism (six studies with 2,718 cases and 3,423 controls) and for the TYMS TS3′-UTR polymorphism (five studies with 1,969 cases and 2,290 controls). The overall odds ratio (OR) and the corresponding 95% confidence interval (CI) showed a statistical association between the TSER polymorphism and breast cancer risk under homozygote comparison (2R/2R vs. non-2R/non-2R; OR 1.25; 95% CI 1.04–1.50), allele contrast (2R vs. non-2R; OR 1.09; 95% CI 1.01–1.19) and the recessive model (OR 1.19; 95% CI 1.01–1.39). In the subgroup analysis by ethnicity, a statistically significant increase in cancer risk was found among Caucasians for homozygote comparison (OR 1.31; 95% CI 1.10–1.57), the allele contrast model (OR 1.12; 95% CI 1.02–1.23) and the dominant model (OR 1.40; 95% CI 1.00–1.95). For the TS3′-UTR polymorphism, significant effects were shown using the allele contrast model (OR 1.33; 95% CI 1.03–1.73). However, the TS3′-UTR polymorphism increased breast cancer risk among Asian women (del6 vs. ins6; OR 1.41; 95% CI 1.01–1.98) but not Caucasian women using the homozygote comparison. In conclusion, our meta-analysis suggests that the TSER polymorphism may increase susceptibility to breast cancer in the Caucasian population and the TS3′-UTR polymorphism may be a genetic determinant for developing breast cancer in the Asian population; therefore, ethnic background should be carefully considered in further studies.

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References

  1. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics, 2007. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  2. Mavaddat N, Antoniou AC, Easton DF, Garcia-Closas M (2010) Genetic susceptibility to breast cancer. Mol Oncol 4:174–191

    Article  PubMed  CAS  Google Scholar 

  3. Kim YI (1999) Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 10:66–88

    Article  PubMed  CAS  Google Scholar 

  4. Larsson SC, Giovannucci E, Wolk A (2007) Folate and risk of breast cancer: a meta-analysis. J Natl Cancer Inst 99:64–76

    Article  PubMed  CAS  Google Scholar 

  5. Ma E, Iwasaki M, Kobayashi M, Kasuga Y, Yokoyama S, Onuma H, Nishimura H, Kusama R, Tsugane S (2009) Dietary intake of folate, vitamin B2, vitamin B6, vitamin B12, genetic polymorphism of related enzymes, and risk of breast cancer: a case–control study in Japan. Nutr Cancer 61:447–456

    Article  PubMed  CAS  Google Scholar 

  6. Rohan TE, Jain MG, Howe GR, Miller AB (2000) Dietary folate consumption and breast cancer risk. J Natl Cancer Inst 92:266–269

    Article  PubMed  CAS  Google Scholar 

  7. Shrubsole MJ, Jin F, Dai Q, Shu XO, Potter JD, Hebert JR, Gao YT, Zheng W (2001) Dietary folate intake and breast cancer risk: results from the Shanghai Breast Cancer Study. Cancer Res 61:7136–7141

    PubMed  CAS  Google Scholar 

  8. Zhang SM, Willett WC, Selhub J, Hunter DJ, Giovannucci EL, Holmes MD, Colditz GA, Hankinson SE (2003) Plasma folate, vitamin B6, vitamin B12, homocysteine, and risk of breast cancer. J Natl Cancer Inst 95:373–380

    Article  PubMed  CAS  Google Scholar 

  9. Stover PJ (2009) One-carbon metabolism-genome interactions in folate-associated pathologies. J Nutr 139:2402–2405

    Article  PubMed  CAS  Google Scholar 

  10. Peters GJ, Backus HH, Freemantle S, van Triest B, Codacci-Pisanelli G, van der Wilt CL, Smid K, Lunec J, Calvert AH, Marsh S, McLeod HL, Bloemena E, Meijer S, Jansen G, van Groeningen CJ, Pinedo HM (2002) Induction of thymidylate synthase as a 5-fluorouracil resistance mechanism. Biochim Biophys Acta 1587:194–205

    PubMed  CAS  Google Scholar 

  11. Marsh S, McKay JA, Cassidy J, McLeod HL (2001) Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int J Oncol 19:383–386

    PubMed  CAS  Google Scholar 

  12. Kawakami K, Omura K, Kanehira E, Watanabe Y (1999) Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 19:3249–3252

    PubMed  CAS  Google Scholar 

  13. Gao CM, Takezaki T, Wu JZ, Liu YT, Ding JH, Li SP, Su P, Hu X, Kai HT, Li ZY, Matsuo K, Hamajima N, Sugimura H, Tajima K (2004) Polymorphisms in thymidylate synthase and methylenetetrahydrofolate reductase genes and the susceptibility to esophageal and stomach cancer with smoking. Asian Pac J Cancer Prev 5:133–138

    PubMed  CAS  Google Scholar 

  14. 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 21:97–102

    Article  PubMed  CAS  Google Scholar 

  15. 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 24:3215–3219

    PubMed  CAS  Google Scholar 

  16. Henriquez-Hernandez LA, Murias-Rosales A, Hernandez Gonzalez A, Cabrera De Leon A, Diaz-Chico BN, Mori De Santiago M, Fernandez Perez L (2009) Gene polymorphisms in TYMS, MTHFR, p53 and MDR1 as risk factors for breast cancer: a case–control study. Oncol Rep 22:1425–1433

    Article  PubMed  CAS  Google Scholar 

  17. Inoue M, Robien K, Wang R, Van Den Berg DJ, Koh WP, Yu MC (2008) Green tea intake, MTHFR/TYMS genotype and breast cancer risk: the Singapore Chinese Health Study. Carcinogenesis 29:1967–1972

    Article  PubMed  CAS  Google Scholar 

  18. Jakubowska A, Gronwald J, Menkiszak J, Gorski B, Huzarski T, Byrski T, Toloczko-Grabarek A, Gilbert M, Edler L, Zapatka M, Eils R, Lubinski J, Scott RJ, Hamann U (2010) BRCA1-associated breast and ovarian cancer risks in Poland: no association with commonly studied polymorphisms. Breast Cancer Res Treat 119:201–211

    Article  PubMed  Google Scholar 

  19. Justenhoven C, Hamann U, Pierl CB, Rabstein S, Pesch B, Harth V, Baisch C, Vollmert C, Illig T, Bruning 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 14:3015–3018

    Article  PubMed  CAS  Google Scholar 

  20. Sangrajrang S, Sato Y, Sakamoto H, Ohnami S, Khuhaprema T, Yoshida T (2010) Genetic polymorphisms in folate and alcohol metabolism and breast cancer risk: a case–control study in Thai women. Breast Cancer Res Treat 123(3):885–893

    Article  PubMed  CAS  Google Scholar 

  21. Suzuki T, Matsuo K, Hirose K, Hiraki A, Kawase T, Watanabe M, Yamashita T, Iwata H, Tajima K (2008) One-carbon metabolism-related gene polymorphisms and risk of breast cancer. Carcinogenesis 29:356–362

    Article  PubMed  CAS  Google Scholar 

  22. 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 28:1504–1509

    Article  PubMed  CAS  Google Scholar 

  23. Zhai X, Gao J, Hu Z, Tang J, Qin J, Wang S, Wang X, Jin G, Liu J, Chen W, Chen F, Wei Q, Shen H (2006) Polymorphisms in thymidylate synthase gene and susceptibility to breast cancer in a Chinese population: a case–control analysis. BMC Cancer 6:138

    Article  PubMed  Google Scholar 

  24. Lau J, Ioannidis JP, Schmid CH (1997) Quantitative synthesis in systematic reviews. Ann Intern Med 127:820–826

    PubMed  CAS  Google Scholar 

  25. Maruti SS, Ulrich CM, Jupe ER, White E (2009) MTHFR C677T and postmenopausal breast cancer risk by intakes of one-carbon metabolism nutrients: a nested case–control study. Breast Cancer Res 11:R91

    Article  PubMed  Google Scholar 

  26. Tao MH, Shields PG, Nie J, Marian C, Ambrosone CB, McCann SE, Platek M, Krishnan SS, Xie B, Edge SB, Winston J, Vito D, Trevisan M, Freudenheim JL (2009) DNA promoter methylation in breast tumors: no association with genetic polymorphisms in MTHFR and MTR. Cancer Epidemiol Biomarkers Prev 18:998–1002

    Article  PubMed  CAS  Google Scholar 

  27. Lincz LF, Scorgie FE, Garg MB, Ackland SP (2007) Identification of a novel single nucleotide polymorphism in the first tandem repeat sequence of the thymidylate synthase 2R allele. Int J Cancer 120:1930–1934

    Article  PubMed  CAS  Google Scholar 

  28. Shi Q, Zhang Z, Neumann AS, Li G, Spitz MR, Wei Q (2005) Case–control analysis of thymidylate synthase polymorphisms and risk of lung cancer. Carcinogenesis 26:649–656

    Article  PubMed  CAS  Google Scholar 

  29. Suzuki T, Matsuo K, Hiraki A, Saito T, Sato S, Yatabe Y, Mitsudomi T, Hida T, Ueda R, Tajima K (2007) Impact of one-carbon metabolism-related gene polymorphisms on risk of lung cancer in Japan: a case control study. Carcinogenesis 28:1718–1725

    Article  PubMed  CAS  Google Scholar 

  30. Rouissi K, Ouerhani S, Oliveira E, Marrakchi R, Cherni L, Ben Othman F, Ben Slama MR, Sfaxi M, Ayed M, Chebil M, Amorim A, Prata MJ, Benammar Elgaaied A (2009) Polymorphisms in one-carbon metabolism pathway genes and risk for bladder cancer in a Tunisian population. Cancer Genet Cytogenet 195:43–53

    Article  PubMed  CAS  Google Scholar 

  31. Xu WH, Long JR, Zheng W, Ruan ZX, Cai Q, Cheng JR, Zhao GM, Xiang YB, Shu XO (2009) Association of thymidylate synthase gene with endometrial cancer risk in a Chinese population. Cancer Epidemiol Biomarkers Prev 18:579–584

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Nature Science Foundation of China (30901788) and Shandong Provincial Nature Science Foundation of China (ZR2010HQ038 and ZR2010HM059).

Conflict of interest

The authors have no financial or personal relationships to disclose that could inappropriately influence or bias this work.

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Authors and Affiliations

  1. Department of Oncology, General Hospital, Jinan Command of the People’s Liberation Army, Shifan Street 25, Tianqiao District, Jinan, 250031, China

    Jun Wang, Baocheng Wang, Jingwang Bi & Jianshi Di

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  1. Jun Wang
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  2. Baocheng Wang
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  4. Jianshi Di
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Correspondence to Jun Wang.

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Wang, J., Wang, B., Bi, J. et al. The association between two polymorphisms in the TYMS gene and breast cancer risk: a meta-analysis. Breast Cancer Res Treat 128, 203–209 (2011). https://doi.org/10.1007/s10549-010-1314-0

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  • DOI: https://doi.org/10.1007/s10549-010-1314-0

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