Polymorphisms

Pharmacogenetics is the study of genetic variations in drug-processing genes and individual responses to drugs.95 It enables the improved identification of patients at higher risk for either disease relapse or chemotherapy-associated side effects.

More than 20 years ago, it was recognized that the activity of thiopurine-S-methyltransferase (TPMT), the enzyme involved in the metabolism of 6-mercaptop-urine and 6-thioguanine, differs among patients and that approximately 1 in 300 individuals demonstrates reduced enzymatic activity.96-100 Molecular testing to identify this polymorphism was developed shortly thereafter101102 and showed good correlation with the enzymatic activity. Based on molecular testing, it has become clear that homozygous carriers for one of the three TPMT mutant alleles experience severe myelo-toxicity and increased risk of relapse due to treatment delays.103 104 Interestingly, patients with the mutated TPMT alleles have a significantly higher risk of developing secondary brain tumors if treated with whole-brain radiation.105 Similarly, there was a trend toward increased risk of secondary AML in patients with decreased enzymatic activity.106

Similarly, single-nucleotide polymorphisms involving four of the enzymes involved in methotrexate metabolism have been implicated in increased relapse risk or toxicity in pediatric ALL patients: methylenete-trahydrofolate reductase,107-111 reduced folate carrier,112-114 thymidylate synthetase,115116 and methyl-enetetrahydrofolate dehydrogenase.111

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