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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)
  • Published : 2014.02.28

Abstract

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.

Keywords

ALL;AML;thymidylate synthase;serine hydroxymethyltransferase;polymorphisms;progression

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