Details

Autor(en) / Beteiligte

• Yang, Jun J
• Landier, Wendy
• Yang, Wenjian
• Liu, Chengcheng
• Hageman, Lindsey
• Cheng, Cheng
• Pei, Deqing
• Chen, Yanjun
• Crews, Kristine R
• Kornegay, Nancy
• Wong, F Lennie
• Evans, William E
• Pui, Ching-Hon
• Bhatia, Smita
• Relling, Mary V

Titel

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

Ist Teil von

• Journal of clinical oncology, 2015-04, Vol.33 (11), p.1235-1242

Ort / Verlag

United States: American Society of Clinical Oncology

Erscheinungsjahr

2015

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. 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. 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. 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.