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Genomewide Approach Validates Thiopurine Methyltransferase Activity Is a Monogenic Pharmacogenomic Trait
1Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
Clinical Pharmacology and Therapeutics
|August 27, 2016
Summary
Thiopurine S-methyltransferase (TPMT) activity in children with leukemia is primarily determined by a single gene. TPMT genetic testing accurately predicts mercaptopurine tolerability, supporting its clinical utility.
Area of Science:
- Pharmacogenomics
- Genetics
- Oncology
Background:
- Thiopurine S-methyltransferase (TPMT) is crucial for metabolizing thiopurine drugs like mercaptopurine.
- Variability in TPMT activity affects drug efficacy and toxicity, particularly in pediatric leukemia patients.
- Understanding the genetic basis of TPMT activity is essential for personalized cancer therapy.
Purpose of the Study:
- To identify genetic determinants of erythrocyte TPMT activity in children with leukemia using a genomewide association study (GWAS).
- To evaluate the association between TPMT genetic variants and mercaptopurine tolerability.
- To assess the utility of lymphoblastoid cell lines (LCLs) for pharmacogenomic discovery compared to patient samples.
Main Methods:
- Conducted a GWAS of TPMT activity in 1,026 children with leukemia.
- Analyzed the association between TPMT genotype and mercaptopurine tolerability in 839 patients.
- Compared SNP discovery in patient samples versus 177 LCLs.
Main Results:
- TPMT was the sole gene reaching genomewide significance for TPMT activity (rs1142345; P = 8.6 × 10-61).
- TPMT clinical genotype significantly predicted mercaptopurine tolerability (P = 2.4 × 10-11).
- LCLs showed limitations for pharmacogenomic discovery, with fewer significant SNPs compared to patient GWAS.
Conclusions:
- TPMT activity in leukemia patients behaves as a monogenic trait, strongly influenced by specific genetic variants.
- TPMT genetic testing is a valuable tool for predicting mercaptopurine tolerability in clinical practice.
- Patient-derived data is superior to LCLs for pharmacogenomic discoveries in this context.
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