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NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia
Univ Hosp, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.
Tech Univ Denmark, Dept Bio & Hlth Informat, Lyngby, Denmark.
Univ Hosp, Rigshosp, Dept Pediat & Adolescent Med, Copenhagen, Denmark.
Univ Copenhagen, Fac Hlth & Med Sci, Dept Publ Hlth, Sect Biostat, Copenhagen, Denmark.
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2018 (English)In: Leukemia, ISSN 0887-6924, E-ISSN 1476-5551, Vol. 32, no 12, p. 2527-2535Article in journal (Refereed) Published
Abstract [en]

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 x 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 x 10(-6) and 1.3 x 10(-3), respectively). The association was mostly driven by differences in (wm)Ery-TGN, but in regression analyses adjusted for wmEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher (wm)DNA-TG (P - 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 or (wm)Ery-TGN/(wm)DNA-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.

Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2018. Vol. 32, no 12, p. 2527-2535
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Cancer and Oncology
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URN: urn:nbn:se:uu:diva-372812DOI: 10.1038/s41375-018-0245-3ISI: 000452538900002PubMedID: 30201983OAI: oai:DiVA.org:uu-372812DiVA, id: diva2:1276906
Available from: 2019-01-09 Created: 2019-01-09 Last updated: 2019-01-09Bibliographically approved

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Harila-Saari, Arja H.

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