Skip to main content
PMC home page
Journal of Clinical Laboratory Analysis logoLink to Journal of Clinical Laboratory Analysis
. 2007 Mar 26;21(2):97–102. doi: 10.1002/jcla.20139

Functional polymorphism of thymidylate synthase, but not of the COMT and IL‐1B genes, is associated with breast cancer

Elif Akisik 1, Nejat Dalay 1,✉
PMCID: PMC6649245  PMID: 17385677

Abstract

Polymorphic variations may affect the rate of gene transcription, the stability of the mRNA, or the quantity and activity of the resulting protein. In this study we evaluated the association between the interleukin‐1B C‐31T, catechol‐O‐methyltransferase Val158Met, and thymidylate synthase (TS) 1494del6 polymorphisms and breast cancer. Each genetic polymorphism was investigated by polymerase chain reaction restriction fragment length polymorphism (PCR‐RFLP) analysis. No significant difference in either the genotype distribution or the allelic frequencies of the IL‐1B and COMT gene polymorphisms was observed between the patient and control groups. For the TS 1494del6 polymorphism a significant difference was observed for both the genotypes (P=0.01) and the allele frequencies (P=0.0097), indicating a decreased risk associated with the variant allele. Our data do not provide evidence for an association between the polymorphic variants of the IL‐1B and COMT genes and breast cancer risk. On the other hand, the TS 1494del6 polymorphism is associated with a significantly lower risk of breast cancer and may be a potential genetic marker. J. Clin. Lab. Anal. 21:97–102, 2007. © 2007 Wiley‐Liss, Inc.

Keywords: IL‐1B, COMT, TS, polymorphism, breast cancer

REFERENCES

  • 1. Sehouli J, Mustea A, Koensgen D, Lichtenegger W. Interleukin‐1 receptor antagonist gene polymorphism in epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 2003;12:1205–1208. [PubMed] [Google Scholar]
  • 2. Zienolddiny S, Ryberg D, Maggini V, Skaug V, Canzian F, Haugen A. Polymorphisms of the interleukin‐1 beta gene are associated with increased risk of non‐small cell lung cancer. Int J Cancer 2004;109:353–356. [DOI] [PubMed] [Google Scholar]
  • 3. El‐Omar EM, Carrington M, Chow WH, et al. Interleukin‐1 polymorphisms associated with increased risk of gastric cancer. Nature 2000;404:398–402. [DOI] [PubMed] [Google Scholar]
  • 4. Hamajima N, Matsuo K, Saito T, et al. Interleukin1 polymorphisms, lifestyle factors, and Helicobacter pylori infection. Jpn J Cancer Res 2001;92:383–389. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Parkhill JM, Hennig BJ, Chapple IL, Heasman PA, Taylor JJ. Association of interleukin gene polymorphisms with early‐onset periodontitis. J Clin Periodontol 2000;27:682–689. [DOI] [PubMed] [Google Scholar]
  • 6. Mwantembe O, Gaillard MC, Barkhuizen M, et al. Ethnic differences in allelic associations of the interleukin‐1 gene cluster in South African patients with inflammatory bowel disease (IBD) and in control individuals. Immunogenetics 2001;52:249–254. [DOI] [PubMed] [Google Scholar]
  • 7. Speirs V, Kerin MJ, Newton CJ, et al. Evidence for transcriptional activation of ER‐α by IL‐1β in breast cancer cells. Int J Oncol 1999;15:1251–1254. [DOI] [PubMed] [Google Scholar]
  • 8. Miller LJ, Kurtzman SH, Anderson K, et al. Interleukin‐1 family expression in human breast cancer: interleukin‐1 receptor antagonist. Cancer Invest 2000;18:293–302. [DOI] [PubMed] [Google Scholar]
  • 9. Yager JD, Liehr JG. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 1996;36:203–232. [DOI] [PubMed] [Google Scholar]
  • 10. Zhu BT, Conney AH. Is 2‐methoxyestradiol an endogenous estrogen metabolite that inhibits mammary carcinogenesis?. Cancer Res 1998;58:2269–2277. [PubMed] [Google Scholar]
  • 11. Watanabe J, Shimada T, Gillam EM, et al. Associations of CYP1B1 genetic polymorphism with incidence to breast and lung cancer. Pharmacogenetics 2000;10:25–33. [DOI] [PubMed] [Google Scholar]
  • 12. Zhu BT. Catechol‐O‐methyltransferase (COMT)‐mediated methylation metabolism of endogenous bioactive catechols and modulation by endobiotics and xenobiotics: importance in pathophysiology and pathogenesis. Curr Drug Metab 2002;3:321–349. [DOI] [PubMed] [Google Scholar]
  • 13. Huh MM, Friedhoff AJ. Multiple molecular forms of catechol‐O‐methyltransferase. Evidence for two distinct forms, and their purification and physical characterization. J Biol Chem 1979;254:299–330. [PubMed] [Google Scholar]
  • 14. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshillboum RM. Human catechol‐O‐methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243–250. [DOI] [PubMed] [Google Scholar]
  • 15. Zhu BT, Conney AH. Functional role of estrogen metabolism in target cells: review and perspectives. Carcinogenesis 1998;19:1–27. [DOI] [PubMed] [Google Scholar]
  • 16. Goodman JE, Lavigne JA, Hengstler JG, et al. COMT genotype, micronutrients in the folate metabolic pathway and breast cancer risk. Carcinogenesis 2001;22:1661–1665. [DOI] [PubMed] [Google Scholar]
  • 17. Garner EI, Stokes EE, Berkowitz RS, Mok SC, Cramer DW. Polymorphisms of the estrogen‐metabolizing genes CYP17 and catechol‐O‐methyltransferase and risk of epithelial ovarian cancer. Cancer Res 2002;62:3058–3062. [PubMed] [Google Scholar]
  • 18. Lavigne JA, Helzlsoue KJ, Huang HY, et al. An association between the allele coding for a low activity variant of catechol‐O‐methyltransferase and risk for breast cancer. Cancer Res 1997;57:5493–5497. [PubMed] [Google Scholar]
  • 19. Kocabas NA, Sardas S, Cholerton S, Daly AK, Karakaya AE. Cytochrome P450 CYP1B1 and catechol‐O‐methyltransferase (COMT) genetic polymorphisms and breast cancer susceptibility in a Turkish population. Arch Toxicol 2002;76:643–649. [DOI] [PubMed] [Google Scholar]
  • 20. Yim DS, Park SK, Yoo KY, et al. Relationship between the Val 158 Met polymorphism of catechol‐O‐methyltransferase and breast cancer. Pharmacogenetics 2001;11:279–286. [DOI] [PubMed] [Google Scholar]
  • 21. Mandola MV, Stoehlmacher J, Zhang W, et al. A 6 bp polymorphism in the thymidylate synthase gene causes message instability and is associated with decreased intratumoral TS mRNA levels. Pharmacogenetics 2004;14:1–9. [DOI] [PubMed] [Google Scholar]
  • 22. Ulrich CM, Bigler J, Velicer CM, Greene EA, Farin FM, Potter JD. Searching expressed sequence tag databases: discovery and confirmation of a common polymorphism in the thymidylate synthase gene. Cancer Epidemiol Biomarkers Prev 2000;9:1381–1385. [PubMed] [Google Scholar]
  • 23. Shibata J, Aiba K, Shibata H, Minowa S, Hirokoshi N. Detection and quantitation of thymidylate synthase mRNA in human colon adenocarcinoma cell line resistant to 5‐fluorouracil by competitive PCR. Anticancer Res 1998;18:1457–1463. [PubMed] [Google Scholar]
  • 24. Kaneda S, Takeishi K, Ayusawa D, Shimizu K, Seno T, Altman S. Role in translation of triple tandemly repeated sequence in the 5′‐untranslated region of human thymidylate synthase mRNA. Nucleic Acids Res 1987;15:1259–1270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25. Hamajima N, Saito T, Matsuo K, Kozaki K, Takahashi T, Tajima K. Polymerase chain reaction with confronting two‐pair primers for polymorphism genotyping. Jpn J Cancer Res 2000;91:865–868. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26. Worda C, Sator MO, Schneeberger C, Jantschev T, Ferlitsch K, Huber JC. Influence of the catechol‐O‐methyltransferase (COMT) codon 158 polymorphism on estrogen levels in women. Hum Reprod 2003;18:262–266. [DOI] [PubMed] [Google Scholar]
  • 27. Smith KC, Bateman AC, Fussell HM, Howell WM. Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 2004;31:167–173. [DOI] [PubMed] [Google Scholar]
  • 28. Yang J, Hu Z, Xu Y, et al. Interleukin‐11B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population. Cancer Lett 2004;215:191–198. [DOI] [PubMed] [Google Scholar]
  • 29. Lee KA, Ki CS, Kim HJ, et al. Novel interleukin 1 beta polymorphism increased the risk of gastric cancer in a Korean population. J Gastroenterol 2004;39:429–433. [DOI] [PubMed] [Google Scholar]
  • 30. Kang WK, Park WS, Chin HM, Park CH. The role of interleukin‐1beta gene polymorphism in the gastric carcinogenesis. Korean J Gastroenterol 2004;44:25–33. [PubMed] [Google Scholar]
  • 31. Gatti LL, Burbano RR, de Assumpcao PP, Smith M de A, Payao SL. Interleukin‐1 beta polymorphisms, Helicobacter pylori infection in individuals from northern Brazil with gastric adenocarcinoma. Clin Exp Med 2004;4:93–98. [DOI] [PubMed] [Google Scholar]
  • 32. Wang Y, Kato N, Hoshida Y, et al. Interleukin‐1beta gene polymorphism associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology 2003;37:65–71. [DOI] [PubMed] [Google Scholar]
  • 33. Ito LS, Iwata H, Hamajima N, et al. Significant reduction in breast cancer risk for Japanese women with interleukin 1B‐31CT/TT relative to CC genotype. Jpn J Clin Oncol 2002;32:398–402. [DOI] [PubMed] [Google Scholar]
  • 34. Kristensen VN, Borresen‐Dale AL. Molecular epidemiology of breast cancer: genetic variation in steroid hormone metabolism. Mutat Res 2000;462:323–333. [DOI] [PubMed] [Google Scholar]
  • 35. Yager J, Liehr J. Molecular mechanisms of estrogen carcinogenesis. Annu Rev Pharmacol Toxicol 1996;36:203–232. [DOI] [PubMed] [Google Scholar]
  • 36. Ball P, Knuppen R. Formation, metabolism and physiological importance of catecholestrogens. Am J Obstet Gynecol 1990;163:2163–2170. [DOI] [PubMed] [Google Scholar]
  • 37. Wen W, Cai Q, Shu XO, et al. Cytochrome P4501B1 and catechol‐O‐methyltransferase genetic polymorphisms and breast cancer risk in Chinese women: results from the Shanghai Breast Cancer Study and a meta‐analysis. Cancer Epidemiol Biomarkers Prev 2005;14:329–335. [DOI] [PubMed] [Google Scholar]
  • 38. Mitrunen RC, Pittman GS, Tse CK, et al. Catechol‐O‐methyltransferase and breast cancer risk. Carcinogenesis 1998;11:1943–1947. [DOI] [PubMed] [Google Scholar]
  • 39. Huang CS, Chern HD, Chang KJ, Cheng CW, Hsu SM, Shen CY. Breast cancer risk associated with genotype polymorphism of the estrogen‐metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Cancer Res 1999;59:4870–4875. [PubMed] [Google Scholar]
  • 40. Thompson PA, Shields PG, Freudenheim JL, et al. Genetic polymorphisms in catechol‐O‐methyltransferase, menopausal status, and breast cancer risk. Cancer Res 1998;58:2107–2110. [PubMed] [Google Scholar]
  • 41. Matsui A, Ikeda T, Enomoto K, et al. Progression of human breast cancers to the metastatic state is linked to genotypes of catechol‐O‐methyltransferase. Cancer Lett 2000;150:23–31. [DOI] [PubMed] [Google Scholar]
  • 42. Millikan RC, Pittman GS, Tse CK, et al. Catechol‐O‐methyltransferase and breast cancer risk. Carcinogenesis 1998;19:1943–1947. [DOI] [PubMed] [Google Scholar]
  • 43. Hong CC, Thompson HJ, Jiang C, et al. Val158Met polymorphism in catechol‐O‐methyltransferase gene associated with risk factors for breast cancer. Cancer Epidemiol Biomarkers Prev 2003;12:838–847. [PubMed] [Google Scholar]
  • 44. Lecomte T, Ferraz JM, Zinzindohoue F, et al. Thymidylate synthase gene polymorphism predicts toxicity in colorectal cancer patients receiving 5‐fluorouracil‐based chemotherapy. Clin Cancer Res 2004;10:5880–5888. [DOI] [PubMed] [Google Scholar]
  • 45. Ulrich CM, Bigler J, Bostick R, Fosdick L, Potter JD. Thymidylate synthase promoter polymorphism, interaction with folate intake, and risk of colorectal adenomas. Cancer Res 2002;62:3361–3364. [PubMed] [Google Scholar]
  • 46. Chen J, Hunter DJ, Stampfer MJ, et al. Polymorphism in the thymidylate synthase promoter enhancer region modifies the risk and survival of colorectal cancer. Cancer Epidemiol Biomarkers Prev 2003;12:958–962. [PubMed] [Google Scholar]

Articles from Journal of Clinical Laboratory Analysis are provided here courtesy of Wiley

RESOURCES