Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia.

Abstract

PURPOSE:

Mercaptopurine (MP) is the mainstay of curative therapy for acute lymphoblastic leukemia (ALL). We performed a genome-wide association study (GWAS) to identify comprehensively the genetic basis of MP intolerance in children with ALL.

PATIENTS AND METHODS:

The discovery GWAS and replication cohorts included 657 and 371 children from two prospective clinical trials. MP dose intensity was a marker for drug tolerance and toxicities and was defined as prescribed dose divided by the planned protocol dose during maintenance therapy; its association with genotype was evaluated using a linear mixed-effects model.

RESULTS:

MP dose intensity varied by race and ethnicity and was negatively correlated with East Asian genetic ancestry (P < .001). The GWAS revealed two genome-wide significant loci associated with dose intensity: rs1142345 in TPMT (Tyr240Cys, present in *3A and *3C variants; P = 8.6 × 10(-9)) and rs116855232 in NUDT15 (P = 8.8 × 10(-9)), with independent replication. Patients with TT genotype at rs116855232 were exquisitely sensitive to MP, with an average dose intensity of 8.3%, compared with those with TC and CC genotypes, who tolerated 63% and 83.5% of the planned dose, respectively. The NUDT15 variant was most common in East Asians and Hispanics, rare in Europeans, and not observed in Africans, contributing to ancestry-related differences in MP tolerance. Of children homozygous for either TPMT or NUDT15 variants or heterozygous for both, 100% required ≥ 50% MP dose reduction, compared with only 7.7% of others.

CONCLUSION:

We describe a germline variant in NUDT15 strongly associated with MP intolerance in childhood ALL, which may have implications for treatment individualization in this disease.

• Authors: Jun J Yang, Wendy Landier, Wenjian Yang, Chengcheng Liu, Lindsey Hageman, Cheng Cheng, Deqing Pei, Yanjun Chen, Kristine R Crews, Nancy Kornegay, F Lennie Wong, William E Evans, Ching-Hon Pui, Smita Bhatia, Mary V Relling
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 33 Issue 11 Pg. 1235-42 (Apr 10 2015) ISSN: 1527-7755 [Electronic] United States
• PMID: 25624441 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by American Society of Clinical Oncology.

Chemical References

• Antimetabolites, Antineoplastic
• Mercaptopurine
• NUDT15 protein, human
• Pyrophosphatases

Topics

• Age Factors
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects)
• Asian People (genetics)
• Drug Dosage Calculations
• Gene Frequency
• Genetic Predisposition to Disease
• Genetic Variation
• Genome-Wide Association Study
• Heredity
• Heterozygote
• Hispanic or Latino (genetics)
• Homozygote
• Humans
• Linear Models
• Mercaptopurine (administration & dosage, adverse effects)
• Pharmacogenetics
• Phenotype
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, ethnology, genetics, metabolism)
• Prospective Studies
• Pyrophosphatases (genetics, metabolism)
• Risk Factors
• Treatment Outcome
• White People (genetics)