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Leukemia. 2018 Dec;32(12):2527-2535. doi: 10.1038/s41375-018-0245-3. Epub 2018 Sep 10.

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

Author information

1
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark.
2
Department of Bio and Health Informatics, Technical University of Denmark, Kongens Lyngby, Denmark.
3
Section of Biostatistics, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Department of Pediatric Hematology and Oncology, H. C. Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.
5
Department of Pediatrics, Landspitali University Hospital, Reykjavík, Iceland.
6
Department of Pediatrics, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
7
Department of Laboratory Medicine, Faculty of Medicine and Health sciences, Children's and Women's Health, Norwegian University of Science and Technology, Trondheim, Norway.
8
Department of Women's and Children's Health, Uppsala University, Uppsala, Sweden.
9
Department of Pediatrics, Institution for Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
10
Clinic of Children's Diseases, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
11
Department of Onco-haematology, Talinn Children's Hospital, Talinn, Estonia.
12
Department of Hematology, University Hospital Rishospitalet, Copenhagen, Denmark.
13
Department of Haematology, Aarhus University Hospital, Aarhus, Denmark.
14
Department of Hematology and Coagulation, Sahlgrenska University Hospital, Göteborg, Sweden.
15
Department of Hematology, Ullevål University Hospital, Faculty Division Ullevål University Hospital, University of Oslo, Oslo, Norway.
16
Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.
17
Hematology, Oncology and Transfusion Medicine Center, Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
18
Clinic of Hematology and Oncology, Tartu University Clinic, Tartu, Estonia.
19
Masonic Cancer Center, Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA.
20
Department of Pediatrics, New York University Medical Center, Perlmutter Cancer Center, New York, NY, USA.
21
Sino-Danish Center for Education and Research, University of Chinese Academy of Sciences, Beijing, China.
22
Department of Pediatrics and Adolescent Medicine, University Hospital Rigshospitalet, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.
23
Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark. kjeld.schmiegelow@regionh.dk.

Abstract

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 (wmDNA-TG/wmEry-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 wmEry-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher wmDNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or wmEry-TGN/wmDNA-TG. rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, rs72846714-A genotype was associated with increased occurrence of relapse-specific NT5C2 gain-of-function mutations that reduce cytosol TGN levels (P = 0.03). These observations highlight the impact of both germline and acquired mutations in drug metabolism and disease trajectory.

PMID:
30201983
DOI:
10.1038/s41375-018-0245-3

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