Format

Send to

Choose Destination
J Clin Oncol. 2015 Apr 10;33(11):1235-42. doi: 10.1200/JCO.2014.59.4671. Epub 2015 Jan 26.

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

Author information

1
Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA. jun.yang@stjude.org.
2
Jun J. Yang, Wenjian Yang, Chengcheng Liu, Cheng Cheng, Deqing Pei, Kristine R. Crews, Nancy Kornegay, William E. Evans, Ching-Hon Pui, and Mary V. Relling, St Jude Children's Research Hospital, Memphis, TN; and Wendy Landier, Lindsey Hageman, Yanjun Chen, F. Lennie Wong, and Smita Bhatia, City of Hope, Duarte, CA.

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.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT00137111 NCT00268528.

PMID:
25624441
PMCID:
PMC4375304
DOI:
10.1200/JCO.2014.59.4671
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Secondary source ID, Grant support

Publication types

MeSH terms

Substances

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center