NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

• Published in: Leukemia 2018-12, Vol.32 (12), p.2527-2535
• Main Authors: Tulstrup, Morten, Grosjean, Marie, Nielsen, Stine Nygaard, Grell, Kathrine, Wolthers, Benjamin Ole, Wegener, Peder Skov, Jonsson, Olafur Gisli, Lund, Bendik, Harila-Saari, Arja, Abrahamsson, Jonas, Vaitkeviciene, Goda, Pruunsild, Kaie, Toft, Nina, Holm, Mette, Hulegårdh, Erik, Liestøl, Sigurd, Griskevicius, Laimonas, Punab, Mari, Wang, Jinhua, Carroll, William L., Zhang, Zeyu, Dalgaard, Marlene D., Gupta, Ramneek, Nersting, Jacob, Schmiegelow, Kjeld
• Format: Article
• Language: English
• Subjects: 45/23; 45/43; 5'-nucleotidase; 6-Mercaptopurine; 6-thioguanine; 692/308/2056; 692/700/1720; Acute lymphoblastic leukemia; Acute myelocytic leukemia; Cancer and Oncology; Cancer och onkologi; Cancer Research; Care and treatment; Childhood; Childhood leukemia; Children; Critical Care Medicine; cytarabine sensitivity; Cytosol; Deoxyribonucleic acid; Development and progression; DNA; Drug metabolism; Erythrocytes; expression; Gene frequency; Genetic aspects; Genetic variation; Genome-wide association studies; Genomes; Genotypes; Health aspects; Hematology; Intensive; Internal Medicine; Leukemia; maintenance therapy; Medicine; Medicine & Public Health; Mercaptopurine; Metabolism; Metabolites; methotrexate; Mutation; Nucleotides; Nutrient interactions; Oncology; Patients; Pediatrics; Pediatrik; Regression analysis; Sequences; Single-nucleotide polymorphism; Therapy; Thioguanine; toxicity
• ISSN: 0887-6924; 1476-5551; 1476-5551
• DOI: 10.1038/s41375-018-0245-3

The antileukaemic drug 6-mercaptopurine is converted into thioguanine nucleotides (TGN) and incorporated into DNA (DNA-TG), the active end metabolite. In a series of genome-wide association studies, we analysed time-weighted means ( wm ) of erythrocyte concentrations of TGN (Ery-TGN) and DNA-TG in 1009 patients undergoing maintenance therapy for acute lymphoblastic leukaemia (ALL). In discovery analyses (454 patients), the propensity for DNA-TG incorporation ( wm DNA-TG/ wm Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P  = 2.09 × 10 −10 , minor allele frequency 15%). In validation analyses (555 patients), this association remained significant during both early and late maintenance therapy ( P  = 8.4 × 10 −6 and 1.3 × 10 −3 , respectively). The association was mostly driven by differences in wm Ery-TGN, but in regression analyses adjusted for wm Ery-TGN ( P