title: Genetic variants of thiopurine and folate metabolic pathways determine 6-MP-mediated hematological toxicity in childhood ALL.
abstract: OBJECTIVE
  The rationale of this study was to explore the contribution of genetic variants of the folate pathway to toxicity of 6-mercaptopurine (6-MP)-mediated hematological toxicity in children with acute lymphoblastic leukemia (ALL) and to explore the interaction of these variants with TPMT and ITPA haplotypes using multifactor dimensionality reduction analysis.
  
  
  METHODS
  Children with ALL (n = 96) were screened for GCPII C1561T, RFC1 G80A, cSHMT C1420T, TYMS 5´-UTR 2R3R, TYMS 3´-UTR ins6/del6, MTHFR C677T, MTR A2756G polymorphisms using PCR-RFLP and PCR-amplified fragment length polymorphism techniques.
  
  
  RESULTS
  GCPII C1561T showed independent association with toxicity. The following synergetic interactions appeared to increase the toxicity of 6-mercaptopurine: TPMT*12 × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A; TPMT CTTAT haplotype × RFC1 G80A × TYMS 2R3R. The genetic variants of thiopurine and folate pathway cumulatively appeared to increase the predictability of toxicity (r(2) = 0.41) in a multiple linear regression model. For the observed toxicity grades of 1, 2, 3 and 4, the respective predicted toxicity grades were 1.65 ± 0.29, 1.68 ± 0.24, 2.56 ± 0.58 and 2.99 ± 1.03, p(trend) < 0.0001.
  
  
  CONCLUSIONS
  Gene-gene interaction between thiopurine and folate pathways inflate the 6-MP-mediated toxicity in Indian children with ALL illustrating the importance of ethnicity in the toxicity of 6-MP.
authors: Department of Medical Oncology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad, Andhra Pradesh, PIN 500082, India.
authors: Patchva
authors: P
authors: Dorababu
authors: Shaik Mohammad
authors: SM
authors: Naushad
authors: Vijay Gandhi
authors: VG
authors: Linga
authors: Sadashivudu
authors: S
authors: Gundeti
authors: Narayana
authors: N
authors: Nagesh
authors: Vijay Kumar
authors: VK
authors: Kutala
authors: Pallu
authors: P
authors: Reddanna
authors: Raghunadharao
authors: R
authors: Digumarti
mesh_terms: D000293:Adolescent; D054316:Biomarkers, Pharmacological; D002648:Child; D002675:Child, Preschool; D005260:Female; D005492:Folic Acid / Q000235:genetics / Q000378:metabolism; D056726:Genetic Association Studies; D043425:Glutamate Carboxypeptidase II / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D015122:Mercaptopurine / Q000627:therapeutic use / Q000633:toxicity*; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008727:Methotrexate / Q000627:therapeutic use; D008780:Methyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics; D011755:Pyrophosphatases / Q000235:genetics*; D000097630:Inosine Triphosphatase
chemical_list: D054316:Biomarkers, Pharmacological; D005492:Folic Acid; D043425:Glutamate Carboxypeptidase II; D015122:Mercaptopurine; D008727:Methotrexate; D008780:Methyltransferases; D011755:Pyrophosphatases; C022745:thiopurine methyltransferase; C511829:ITPA protein, human; D000097630:Inosine Triphosphatase