Abstract
DOI:
10.26650/experimed.2018.18005
Objective: The enzyme thymidylate synthase
(TS) in the folate metabolism catalyzes the conversion of deoxyuridine
monophosphate (dUMP) to deoxythymidine monophosphate (dTMP). It provides a
certain balance of deoxynucleotides required for DNA synthesis in the cell.
Inhibition of the enzyme showed that abnormal chromosomal breakage and
apoptosis occurred. The enzyme, which is necessary for proliferating cells,
also targeted different cancer drugs. The TS gene at chromosome 18p11.32
contains the polymorphic repeat region just upstream of the ATG starting site.
This polymorphism, consisting of double or triple repeats of the 28-base length
sequence, has been shown to differ in gene expression in vitro and in vivo.
Similar studies have investigated the relationship between many types of cancer
and cancer drug use and TS polymorphism. In this study, the role of TS promoter
polymorphism in acute leukemia etiology (acute myeloid leukemia and acute
lymphoblastic leukemia) in the Turkish population was investigated.
Material and Method: For this purpose, a
pediatric acute lymphoblastic leukemia (ALL) case admitted to our unit (n=110)
and agorose gel electrophoresis after PCR using region-specific primers with
DNA obtained from pediatric and adult acute myeloid leukemia (AML) (n=126) TS
polymorphic alleles consisting of two or three repetitions were determined. The
results were compared with the results of healthy control (n=133) cases, and we
questioned whether TS gene polymorphism is a risk factor.
Results: Statistical analyses were
performed using the Fisher exact test in the program SPSS, and the 2T/2T
genotype was a risk factor in the formation of ALL (p=0.048).
Conclusion: It was observed that other
genotypes did not have a risk for ALL and AML formations.
References
- 1. Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological malignancies. Ann Oncol 2007;18 (Suppl. 1): i3 -i8. 2. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277- 300. 3. Descatha A, Jenabian A, Conso F, et al. Occupational exposures and haematological malignancies: overview on human recent data. Cancer Causes Control 2005; 16: 939-53. 4. Irigaray P, Newby JA, Clapp R, et al. Lifestyle-related factors and environmental agents causing cancer: an overview. Biomed Pharmacother 2007; 61: 640-58. 5. Skibola CF, Curry JD, Nieters A. Genetic susceptibility to lymphoma. Haematologica 2007; 92: 960- 9 69. 6. Koppen IJ, Hermans FJ, Kaspers GJ. Folate related gene [6] polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 2010; 148: 3-14. 7. Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 2002; 359: 1033-34. 8. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191-7. 9. Hori T, Ayusawa D, Shimizu K, Koyama H, et al. Chromosome breakage induced by thymidylate stress in thymidylate synthase-negative mutants of mouse FM3A cells. Cancer Res. 1984; 44: 703-9. 10. Kim YI. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 1999,10: 66-88. 11. Hishida A, Matsuo K, Hamajima N, Ito H, et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 2003; 88: 159-66. 12. Horie N, Aiba H, Oguro K, Hojo H, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5’-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191-7. 13. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1: 65-70. 14. Kawakami K, Omura K, Kanehira E and Watanabe Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249-52. 15. Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011; 34: 101-9. 16. McCullough ML, Giovannucci EL. Diet and cancer prevention. Oncogene 2004; 23: 6349-64. 17. Sauer J, Mason JB, Choi SW. Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care 2009; 12: 30-6. 18. Lehman NL. Future potential of thymidylate synthase inhibitors in cancer therapy. Expert Opin Investig Drugs 2002; 11: 1775-87. 19. Lightfoot TJ, Skibola CF, Willett EV, et al. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Cancer Epidemiol Biomarkers Prev 2005; 14: 2999-3003. 20. Hishida A, Matsuo K, Hamajima N, et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 2003; 88: 159-66. 21. Skibola CF, Smith MT, Hubbard A, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 2002; 99: 3786-91. 22. De Jonge R, Hooijberg JH, van Zelst BD, et al. Eff ect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood 2005; 106: 717-20. 23. Skibola CF, Forrest MS, Coppede F, et al. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 2004; 104: 2155-62. 24. 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: 319-27. 25. Lincz LF, Scorgie FE, Garg MB, et al. Identifi cation of a novel single nucleotide polymorphism in the fi rst tandem repeat sequence of the thymidylate synthase 2R allele. Int J Cancer 2007; 120: 1930-4. 26. Yu Weng, Jun Zhang, Xue Tang, Xinyou Xie, Guangdi Chen. Thymidylate synthase polymorphisms and hematological cancer risk: a meta-analysis. Leuk Lymphoma 2012; 53: 1345-51. 27. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030-43.
Abstract
DOI:
10.26650/experimed.2018.18005
Amaç: Folat metabolizması içerisinde yer alan
timidilat sentaz (TS) enzimi, deoksiüridin monofosfatın (dUMP), deoksitimidin
monofosfata (dTMP) dönüşümünü katalizlemektedir. Hücre içerisinde DNA sentezi
için gerekli olan deoksinükleotidlerin belirli bir denge de bulunmasını
sağlamaktadır. Enzimin inhibisyonu sonucu anormal kromozom kırıklarının
oluştuğu ve hücre ölümünün gerçekleştiği gösterilmiştir. Çoğalan hücreler için
çok gerekli olan enzim aynı zaman da değişik kanser ilaçlarına da hedef
olmaktadır. Kromozom 18p11.32 de bulunan TS geni, ATG başlama bölgesinin hemen
üzerinde polimorfik tekrar bölgesi içermektedir. 28 bazlık tekrar dizisinin
ikili veya üçlü tekrarından oluşan bu polimorfizmin, in vitro ve in vivo olarak
gen ekspresyonunda farklılık oluşturduğu gösterilmiştir. Benzeri çalışmalar ile
pek çok kanser türü ve kanser ilacı kullanımı ile TS polimorfizmi ilişkisi
sorgulanmıştır. Bu çalışmada Türk populasyonunda akut lösemi etiyolojisinde
(Akut myeloid lösemi ve Akut lenfoblastik lösemi) TS promoter polimorfizminin
rolünün araştırılması amaçlanmıştır.
Yöntemler: Çocukluk çağı akut lenfoblastik
lösemi (ALL) (n=110) ve çocukluk çağı ve erişkin akut myeloid lösemi (AML)
(n=126) olgularından elde edilen DNA’larla bölgeye
özgü primerler kullanılarak yapılan PZR sonrası agoroz jel elektroforezi analizi
ile iki veya üç tekrardan oluşan TS polimorfik allelleri belirlendi. Sonuçlar
sağlıklı kontrol (n=133) olgularının sonuçları ile karşılaştırarak
istatistiksel olarak TS gen polimorfizminin bir risk oluşturup oluşturmadığını
sorgulandı. İstatistiksel analizler, SPSS programındaki Fisher’s exact test kullanılarak yapıldı.
Bulgular: AML olgularında TS promoter
polimorfizmi ile ilişki bulunmadı. Çocukluk çağı ALL olgularında 2T/2T genotipi
anlamlı düzeyde yüksek bulundu (p=0,048).
Sonuç: Çalışmamız ALL gelişiminde, 2T/2T
genotipinin bir risk faktörü olduğunu fakat diğer genotiplerin ALL ve AML
oluşumunda bir risk oluşturmadığını göstermiştir.
Keywords
References
- 1. Rodriguez-Abreu D, Bordoni A, Zucca E. Epidemiology of hematological malignancies. Ann Oncol 2007;18 (Suppl. 1): i3 -i8. 2. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin 2010; 60: 277- 300. 3. Descatha A, Jenabian A, Conso F, et al. Occupational exposures and haematological malignancies: overview on human recent data. Cancer Causes Control 2005; 16: 939-53. 4. Irigaray P, Newby JA, Clapp R, et al. Lifestyle-related factors and environmental agents causing cancer: an overview. Biomed Pharmacother 2007; 61: 640-58. 5. Skibola CF, Curry JD, Nieters A. Genetic susceptibility to lymphoma. Haematologica 2007; 92: 960- 9 69. 6. Koppen IJ, Hermans FJ, Kaspers GJ. Folate related gene [6] polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. Br J Haematol 2010; 148: 3-14. 7. Krajinovic M, Costea I, Chiasson S. Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet 2002; 359: 1033-34. 8. Horie N, Aiba H, Oguro K, Hojo H, Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191-7. 9. Hori T, Ayusawa D, Shimizu K, Koyama H, et al. Chromosome breakage induced by thymidylate stress in thymidylate synthase-negative mutants of mouse FM3A cells. Cancer Res. 1984; 44: 703-9. 10. Kim YI. Folate and carcinogenesis: evidence, mechanisms, and implications. J Nutr Biochem 1999,10: 66-88. 11. Hishida A, Matsuo K, Hamajima N, Ito H, et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 2003; 88: 159-66. 12. Horie N, Aiba H, Oguro K, Hojo H, et al. Functional analysis and DNA polymorphism of the tandemly repeated sequences in the 5’-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct Funct 1995; 20: 191-7. 13. Pullarkat ST, Stoehlmacher J, Ghaderi V, Xiong YP, et al. Thymidylate synthase gene polymorphism determines response and toxicity of 5-FU chemotherapy. Pharmacogenomics J 2001; 1: 65-70. 14. Kawakami K, Omura K, Kanehira E and Watanabe Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res 1999; 19: 3249-52. 15. Duthie SJ. Folate and cancer: how DNA damage, repair and methylation impact on colon carcinogenesis. J Inherit Metab Dis 2011; 34: 101-9. 16. McCullough ML, Giovannucci EL. Diet and cancer prevention. Oncogene 2004; 23: 6349-64. 17. Sauer J, Mason JB, Choi SW. Too much folate: a risk factor for cancer and cardiovascular disease? Curr Opin Clin Nutr Metab Care 2009; 12: 30-6. 18. Lehman NL. Future potential of thymidylate synthase inhibitors in cancer therapy. Expert Opin Investig Drugs 2002; 11: 1775-87. 19. Lightfoot TJ, Skibola CF, Willett EV, et al. Risk of non-Hodgkin lymphoma associated with polymorphisms in folate-metabolizing genes. Cancer Epidemiol Biomarkers Prev 2005; 14: 2999-3003. 20. Hishida A, Matsuo K, Hamajima N, et al. Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica 2003; 88: 159-66. 21. Skibola CF, Smith MT, Hubbard A, et al. Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 2002; 99: 3786-91. 22. De Jonge R, Hooijberg JH, van Zelst BD, et al. Eff ect of polymorphisms in folate-related genes on in vitro methotrexate sensitivity in pediatric acute lymphoblastic leukemia. Blood 2005; 106: 717-20. 23. Skibola CF, Forrest MS, Coppede F, et al. Polymorphisms and haplotypes in folate-metabolizing genes and risk of non-Hodgkin lymphoma. Blood 2004; 104: 2155-62. 24. 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: 319-27. 25. Lincz LF, Scorgie FE, Garg MB, et al. Identifi cation of a novel single nucleotide polymorphism in the fi rst tandem repeat sequence of the thymidylate synthase 2R allele. Int J Cancer 2007; 120: 1930-4. 26. Yu Weng, Jun Zhang, Xue Tang, Xinyou Xie, Guangdi Chen. Thymidylate synthase polymorphisms and hematological cancer risk: a meta-analysis. Leuk Lymphoma 2012; 53: 1345-51. 27. Pui CH, Robison LL, Look AT. Acute lymphoblastic leukaemia. Lancet 2008; 371: 1030-43.
Details
| Primary Language | English |
|---|---|
| Subjects | Clinical Sciences |
| Journal Section | Research Article |
| Authors | |
| Publication Date | December 2, 2018 |
| Submission Date | October 24, 2018 |
| Published in Issue | Year 2018 Volume: 8 Issue: 3 |
