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

Morten Tulstrup; Marie Grosjean; Stine Nygaard Nielsen; Kathrine Grell; Benjamin Ole Wolthers; Peder Skov Wegener; Olafur Gisli Jonsson; Bendik Lund; Arja Harila-Saari; Jonas Abrahamsson; Goda Vaitkeviciene; Kaie Pruunsild; Nina Toft; Mette Holm; Erik Hulegårdh; Sigurd Liestøl; Laimonas Griskevicius; Mari Punab; Jinhua Wang; William L Carroll; Zeyu Zhang; Marlene D. Dalgaard; Ramneek Gupta; Jacob Nersting; Kjeld Schmiegelow

doi:10.1038/s41375-018-0245-3

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

Morten Tulstrup, Marie Grosjean, Stine Nygaard Nielsen, Kathrine Grell, Benjamin Ole Wolthers, Peder Skov Wegener, Olafur Gisli Jonsson, Bendik Lund, Arja Harila-Saari, Jonas Abrahamsson, Goda Vaitkeviciene, Kaie Pruunsild, Nina Toft, Mette Holm, Erik Hulegårdh, Sigurd Liestøl, Laimonas Griskevicius, Mari Punab, Jinhua Wang, William L CarrollZeyu Zhang, Marlene D. Dalgaard, Ramneek Gupta, Jacob Nersting, Kjeld Schmiegelow

6 Citations (Scopus)

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.

Original language	English
Journal	Leukemia
Volume	32
Pages (from-to)	2527-2535
Number of pages	9
ISSN	0887-6924
DOIs	https://doi.org/10.1038/s41375-018-0245-3
Publication status	Published - 1 Dec 2018

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Tulstrup, M., Grosjean, M., Nielsen, S. N., Grell, K., Wolthers, B. O., Wegener, P. S., Jonsson, O. G., Lund, B., Harila-Saari, A., Abrahamsson, J., Vaitkeviciene, G., Pruunsild, K., Toft, N., Holm, M., Hulegårdh, E., Liestøl, S., Griskevicius, L., Punab, M., Wang, J., ... Schmiegelow, K. (2018). NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia. Leukemia, 32, 2527-2535. https://doi.org/10.1038/s41375-018-0245-3

Tulstrup, M, Grosjean, M, Nielsen, SN, Grell, K, Wolthers, BO, Wegener, PS, Jonsson, OG, Lund, B, Harila-Saari, A, Abrahamsson, J, Vaitkeviciene, G, Pruunsild, K, Toft, N, Holm, M, Hulegårdh, E, Liestøl, S, Griskevicius, L, Punab, M, Wang, J, Carroll, WL, Zhang, Z, Dalgaard, MD, Gupta, R, Nersting, J & Schmiegelow, K 2018, 'NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia', Leukemia, vol. 32, pp. 2527-2535. https://doi.org/10.1038/s41375-018-0245-3

@article{b5058686405444fab4a80b962a31e087,

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

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.",

author = "Morten Tulstrup and Marie Grosjean and Nielsen, {Stine Nygaard} and Kathrine Grell and Wolthers, {Benjamin Ole} and Wegener, {Peder Skov} and Jonsson, {Olafur Gisli} and Bendik Lund and Arja Harila-Saari and Jonas Abrahamsson and Goda Vaitkeviciene and Kaie Pruunsild and Nina Toft and Mette Holm and Erik Huleg{\aa}rdh and Sigurd Liest{\o}l and Laimonas Griskevicius and Mari Punab and Jinhua Wang and Carroll, {William L} and Zeyu Zhang and Dalgaard, {Marlene D.} and Ramneek Gupta and Jacob Nersting and Kjeld Schmiegelow",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41375-018-0245-3",

language = "English",

volume = "32",

pages = "2527--2535",

journal = "Leukemia",

issn = "0887-6924",

publisher = "nature publishing group",

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TY - JOUR

T1 - NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia

AU - Tulstrup, Morten

AU - Grosjean, Marie

AU - Nielsen, Stine Nygaard

AU - Grell, Kathrine

AU - Wolthers, Benjamin Ole

AU - Wegener, Peder Skov

AU - Jonsson, Olafur Gisli

AU - Lund, Bendik

AU - Harila-Saari, Arja

AU - Abrahamsson, Jonas

AU - Vaitkeviciene, Goda

AU - Pruunsild, Kaie

AU - Toft, Nina

AU - Holm, Mette

AU - Hulegårdh, Erik

AU - Liestøl, Sigurd

AU - Griskevicius, Laimonas

AU - Punab, Mari

AU - Wang, Jinhua

AU - Carroll, William L

AU - Zhang, Zeyu

AU - Dalgaard, Marlene D.

AU - Gupta, Ramneek

AU - Nersting, Jacob

AU - Schmiegelow, Kjeld

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41375-018-0245-3

DO - 10.1038/s41375-018-0245-3

M3 - Journal article

C2 - 30201983

SN - 0887-6924

VL - 32

SP - 2527

EP - 2535

JO - Leukemia

JF - Leukemia

ER -

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

Abstract

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