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

Artikel i vetenskaplig tidskrift
Författare M. Tulstrup
M. Grosjean
S. N. Nielsen
K. Grell
B. O. Wolthers
P. S. Wegener
O. G. Jonsson
B. Lund
A. Harila-Saari
Jonas Abrahamsson
G. Vaitkeviciene
K. Pruunsild
N. Toft
M. Holm
E. Hulegardh
S. Liestol
L. Griskevicius
M. Punab
J. H. Wang
W. L. Carroll
Z. Y. Zhang
M. D. Dalgaard
R. Gupta
J. Nersting
K. Schmiegelow
Publicerad i Leukemia
Volym 32
Nummer/häfte 12
Sidor 2527-2535
ISSN 0887-6924
Publiceringsår 2018
Publicerad vid Institutionen för kliniska vetenskaper, Avdelningen för pediatrik
Sidor 2527-2535
Språk en
Länkar dx.doi.org/10.1038/s41375-018-0245-...
Ämnesord cytarabine sensitivity, maintenance therapy, children, 5'-nucleotidase, mercaptopurine, expression, 6-mercaptopurine, 6-thioguanine, methotrexate, toxicity
Ämneskategorier Cancer och onkologi, Pediatrik

Sammanfattning

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.

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