Abstract

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.

Highlights

  • The etiology of acute leukemia is complex involving mutations (Abdel-Wahab et al, 2013), chromosomal rearrangements (Chapiro et al, 2013), epigenetic alterations (Estey, 2013) etc

  • In view of limited studies from India, discrepant results in association studies worldwide, we proposed to investigate the impact of thymidylate synthase (TYMS) 5’-UTR 28bp tandem repeat and cytosolic serine hydroxymethyltransferase (cSHMT) C1420T polymorphisms on the susceptibility to acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in South Indian subjects

  • Studies reported that the high levels of uracil misincorporation followed by extensive repair by uracil DNA glycosylase increase double strand DNA breaks that might contribute to chromosomal instability, translocation, and chromosomal aberrations which might contribute to leukemia risk (Melnyk et al, 1999)

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Summary

Introduction

The etiology of acute leukemia is complex involving mutations (Abdel-Wahab et al, 2013), chromosomal rearrangements (Chapiro et al, 2013), epigenetic alterations (Estey, 2013) etc. Several studies have been conducted worldwide on different genetic polymorphisms of the folate pathway for possible association with acute leukemias. Bolufer et al reported reduced risk for acute lymphoblastic leukemia (ALL) in subjects with TYMS 2R 3R genotype and risk reduction was more predominant in the presence of cSHMT C1420T polymorphism (Bolufer et al, 2006). The possibility exists that an enhanced flux of methylene THF and resultant increase in dTMP production in the DNA synthesis pathway due to TYMS tandem repeat polymorphisms might work protectively against oncogenesis of lymphoid malignancies (Hishida et al, 2003). In view of limited studies from India, discrepant results in association studies worldwide, we proposed to investigate the impact of TYMS 5’-UTR 28bp tandem repeat and cSHMT C1420T polymorphisms on the susceptibility to ALL and AML in South Indian subjects

Materials and Methods
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