- Volume 15 Issue 4
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Association of Thymidylate Synthase 5'-UTR 28bp Tandem Repeat and Serine Hydroxymethyltransfarase C1420T Polymorphisms with Susceptibility to Acute Leukemia
- Dunna, Nageswara Rao (School of Chemical and Biotechnology, SASTRA University) ;
- Naushad, Shaik Mohammad (School of Chemical and Biotechnology, SASTRA University) ;
- Vuree, Sugunakar (Department of Genetics, Osmania University) ;
- Anuradha, Cingeetham (Department of Genetics, Osmania University) ;
- Sailaja, Kagita (Department of Medical Oncology, Nizam's Institute of Medical Sciences) ;
- Surekha, Damineni (Department of Genetics, Osmania University) ;
- Rao, Digumarti Raghunadha (Department of Medical Oncology, Nizam's Institute of Medical Sciences) ;
- Vishnupriya, Satti (Department of Genetics, Osmania University)
- 발행 : 2014.02.28
Background: The current study was aimed to elucidate the association of thymidylate synthase (TYMS) 5'-UTR 28bp tandem repeat and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T polymorphisms with acute leukemia in South Indian subjects. A total of 812 subjects [523 healthy controls, 148 acute lymphoblastic leukemia (ALL) cases and 141 acute myeloid leukemia (AML) cases] were screened for TYMS 5'-UTR 28bp tandem repeat and cSHMT C1420T using PCR-AFLP and PCR-with confronting two-pair primers (CTPP) approaches. TYMS 5'-UTR 2R allele frequencies of controls, ALL and AML cases were 35.3%, 28.0% and 30.1% respectively. This polymorphism conferred protection against ALL (OR: 0.71, 95%CI: 0.53-0.96) while showing no statistically significant association with AML (OR: 0.79, 95%CI: 0.58, 1.07). The cSHMT variant allele (T-) frequencies of ALL and AML cases (6.42% and 5.68% respectively) were significantly lower compared to controls (58.3%). This polymorphism conferred protection against ALL (OR: 0.049, 95%CI: 0.029-0.081) and AML (OR: 0.043, 95%CI: 0.025-0.074). The TYMS 5'-UTR 2R2R genotype was associated with a lower total leukocyte count, smaller percentage of blasts, and more adequate platelet count compared to 2R3R and 3R3R genotypes in ALL cases. No such genotype-dependent differences were observed in AML cases. ALL cases carrying the cSHMT C1420T polymorphism showed higher disease free survival compared to those with the wild genotype. To conclude, the TYMS 5'-UTR 28bp tandem repeat reduces risk for ALL while cSHMT C1420T reduces risk for both ALL and AML. Both also influence disease progression in ALL.
ALL;AML;thymidylate synthase;serine hydroxymethyltransferase;polymorphisms;progression
- Kawakami K, Omura K, Kanehira E, et al (1999). Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res, 19, 3249-52.
- Kim HN, Kim YK, Lee IK, et al (2009). Association between polymorphisms of folate-metabolizing enzymes and hematological malignancies. Leuk Res, 33, 82-7. https://doi.org/10.1016/j.leukres.2008.07.026
- Hu YC, Komorowski RA, Graewin S, et al (2003). Thymidylate synthase expression predicts the response to 5-fluorouracilbased adjuvant therapy in pancreatic cancer. Clin Cancer Res, 9, 4165-71.
- Ingraham HA, Dickey L, Goulian M (1986). DNA fragmentation and cytotoxicity from increased cellular deoxyuridylate. Biochem, 25, 3225-30. https://doi.org/10.1021/bi00359a022
- Krajinovic M, Costea I, Chiasson S (2002). Polymorphism of the thymidylate synthase gene and outcome of acute lymphoblastic leukaemia. Lancet, 359, 1033-4. https://doi.org/10.1016/S0140-6736(02)08065-0
- Lahiri DK, Nurnberger JI Jr (1991). A rapid non-enzymatic method for the preparation of HMW from blood RFLP studies. Nucleic Acid Res, 19, 5444. https://doi.org/10.1093/nar/19.19.5444
- Marcuello E, Altes A, del Rio E, et al (2004). Single nucleotide polymorphism in the 5' tandem repeat sequences of thymidylate synthase gene predicts for response to fluorouracil-based chemotherapy in advanced colorectal cancer patients. Int J Cancer, 112, 733-7. https://doi.org/10.1002/ijc.20487
- Melnyk S, Pogribna M, Miller BJ, et al (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, 35-44. https://doi.org/10.1016/S0304-3835(99)00213-X
- Mohammad NS, Jain JM, Chintakindi KP et al (2009). Aberrations in folate metabolic pathway and altered susceptibility to autism. Psychiatr Genet, 19, 171-6. https://doi.org/10.1097/YPG.0b013e32832cebd2
- Abdel-Wahab O, Levine RL (2013). Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia. Blood, 121, 3563-72. https://doi.org/10.1182/blood-2013-01-451781
- Bolufer P, Barragan E, Collado M, et al (2006). Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression. Leuk Res, 30, 1471-91. https://doi.org/10.1016/j.leukres.2006.01.016
- Chapiro E, Radford-Weiss I, Cung HA, et al (2013). Chromosomal translocations involving the IGH@ locus in B-cell precursor acute lymphoblastic leukemia: 29 new cases and a review of the literature. Cancer Genet, 206, 162-73. https://doi.org/10.1016/j.cancergen.2013.04.004
- Estey EH (2013). Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia. Leukemia, 27, 1803-12. https://doi.org/10.1038/leu.2013.173
- Hamajima N, Saito T, Matsuo K, et al (2000). Polymerase chain reaction with confronting two-pair primers for polymorphism genotyping. Jpn J Cancer Res, 91, 865-8. https://doi.org/10.1111/j.1349-7006.2000.tb01026.x
- Hishida A, Matsuo K, Hamajima N, et al (2003). Associations between polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and susceptibility to malignant lymphoma. Haematologica, 88, 159-66.
- Horie N, Aiba H, Oguro K, et al (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 Struct Funct, 20, 191-7. https://doi.org/10.1247/csf.20.191
- Skibola CF, Smith MT, Hubbard A, et al (2002). Polymorphisms in the thymidylate synthase and serine hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood, 99, 3786-91. https://doi.org/10.1182/blood.V99.10.3786
- Welsh SJ, Titley J, Brunton L, et al (2000). Comparison of thymidylate synthase (TS) protein up-regulation after exposure to TS inhibitors in normal and tumor cell lines and tissues. Clin Cancer Res, 6, 2538-46.
- Molina JR, Adjei AA (2003). The role of Pemetrexed (Alimta , LY231514) in lung cancer therapy. Clin Lung Cancer, 5, 21-7 https://doi.org/10.3816/CLC.2003.n.017
- Naushad SM, Pavani A, Digumarti RR, et al (2011). Epistatic interactions between loci of one-carbon metabolism modulate susceptibility to breast cancer. Mol Biol Rep, 38, 4893-901. https://doi.org/10.1007/s11033-010-0631-z
- Nazki FH, Masood A, Banday MA, et al (2012). Thymidylate synthase enhancer region polymorphism not related to susceptibility to acute lymphoblastic leukemia in the Kashmir population. Genet Mol Res, 11, 906-17. https://doi.org/10.4238/2012.April.10.6
- Rots MG, Willey JC, Jansen G, et al (2000). mRNA expression levels of methotrexate resistance-related proteins in childhood leukemia as determined by a standardized competitive template-based RT-PCR method. Leukemia, 14, 2166-75. https://doi.org/10.1038/sj.leu.2401943
- Snell K, Baumann U, Byrne PC, et al (2000). The genetic organization and protein crystallographic structure of human serine hydroxymethyltransferase. Adv Enzyme Regul, 40, 353-403. https://doi.org/10.1016/S0065-2571(99)00035-7
- Vijaya Lakshmi SV, Naushad SM, Seshagiri Rao D, et al (2011). Oxidative stress is associated with genetic polymorphisms in one-carbon metabolism in coronary artery disease. Cell Biochem Biophys, 67, 353-61
- Wang Y, Guo W, He Y, et al (2007). Association of MTHFR C677T and SHMT(1) C1420T with susceptibility to ESCC and GCA in a high incident region of Northern China. Cancer Causes Control, 18, 143-52. https://doi.org/10.1007/s10552-006-0097-4
- Wang YM, Guo W, Zhang XF, et al (2006). Correlations between serine hydroxymethyltransferase 1 C1420T polymorphisms and susceptibilities to esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma. Ai Zheng, 25, 281-6.
- Allogeneic Hemopietic Stem Cell Transplants for the Treatment of B Cell Acute Lymphocytic Leukemia vol.15, pp.15, 2014, https://doi.org/10.7314/APJCP.2014.15.15.6127
- Wilms tumor gene single nucleotide polymorphism rs16754 predicts a favorable outcome in children with acute lymphoblastic leukemia vol.141, pp.12, 2015, https://doi.org/10.1007/s00432-015-2018-y