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

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  • Morten Tulstrup, Rigshospitalet
  • ,
  • Marie Grosjean, Danmarks Tekniske Universitet
  • ,
  • Stine Nygaard Nielsen, Department of Pediatrics and Adolescent Medicine, Rigshospitalet
  • ,
  • Kathrine Grell, Rigshospitalet, Københavns Universitet
  • ,
  • Benjamin Ole Wolthers, Rigshospitalet
  • ,
  • Peder Skov Wegener, Odense Universitetshospital
  • ,
  • Olafur Gisli Jonsson, Landspitali University Hospital, Reykjavik
  • ,
  • Bendik Lund, St Olavs Hospital, Trondheim University Hospital, Norwegian University of Science and Technology
  • ,
  • Arja Harila-Saari, Uppsala University
  • ,
  • Jonas Abrahamsson, Sahlgrenska Academy
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  • Goda Vaitkeviciene, Vilnius University
  • ,
  • Kaie Pruunsild, Talinn Children’s Hospital
  • ,
  • Nina Toft, Københavns Universitet
  • ,
  • Mette Holm
  • Erik Hulegårdh, Gøteborg Transplantationscenter, Sahlgrenska Universitetssjukhuset
  • ,
  • Sigurd Liestøl, Eastern and Southern Norway
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  • Laimonas Griskevicius, Vilnius University
  • ,
  • Mari Punab, Tartu University Clinics
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  • Jinhua Wang, University of Minnesota Twin Cities
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  • William L. Carroll, New York University Medical Center
  • ,
  • Zeyu Zhang, Danmarks Tekniske Universitet, University of Chinese Academy of Sciences
  • ,
  • Marlene D. Dalgaard, Danmarks Tekniske Universitet
  • ,
  • Ramneek Gupta, Department of Bio and Health Informatics
  • ,
  • Jacob Nersting, Rigshospitalet
  • ,
  • Kjeld Schmiegelow, Department of Pediatrics and Adolescent Medicine, Rigshospitalet, Københavns Universitet

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.

OriginalsprogEngelsk
TidsskriftLeukemia
Vol/bind32
Nummer12
Sider (fra-til)2527-2535
Antal sider9
ISSN0887-6924
DOI
StatusUdgivet - dec. 2018

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