Journal article
NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia
University of Copenhagen1
Tallinn Children’s Hospital2
Aarhus University3
University of Oslo4
University of Tartu5
University of Minnesota Twin Cities6
New York University7
Technical University of Denmark8
Disease Intelligence and Molecular Evolution, Department of Bio and Health Informatics, Technical University of Denmark9
Department of Bio and Health Informatics, Technical University of Denmark10
Copenhagen University Hospital Herlev and Gentofte11
University of Southern Denmark12
Landspitali University Hospital13
Norwegian University of Science and Technology14
Uppsala University15
University of Gothenburg16
Vilnius University17
...and 7 moreThe 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.
Language: | English |
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Publisher: | Nature Publishing Group UK |
Year: | 2018 |
Pages: | 2527-2535 |
ISSN: | 14765551 and 08876924 |
Types: | Journal article |
DOI: | 10.1038/s41375-018-0245-3 |
ORCIDs: | Gupta, Ramneek , 0000-0002-7444-7652 and 0000-0001-6398-6979 |
5'-Nucleotidase Adolescent Antimetabolites, Antineoplastic Child Child, Preschool DNA Female Gene Frequency Genome-Wide Association Study Genotype Germ Cells Humans Infant Male Mercaptopurine NT5C2 protein, human Neoplasm Recurrence, Local Polymorphism, Single Nucleotide Precursor Cell Lymphoblastic Leukemia-Lymphoma Recurrence Thioguanine