NT5C2 germline variants alter thiopurine metabolism and are associated with acquired NT5C2 relapse mutations in childhood acute lymphoblastic leukaemia.
Morten TulstrupMarie GrosjeanStine Nygaard NielsenKathrine GrellBenjamin Ole WolthersPeder Skov WegenerOlafur Gisli JonssonBendik LundArja Harila-SaariJonas AbrahamssonGoda VaitkevicieneKaie PruunsildNina ToftMette HolmErik HulegårdhSigurd LiestølLaimonas GriskeviciusMari PunabJinhua WangWilliam L CarrollZeyu ZhangMarlene D DalgaardRamneek GuptaJacob NerstingKjeld SchmiegelowPublished in: Leukemia (2018)
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.
Keyphrases
- end stage renal disease
- circulating tumor
- chronic kidney disease
- cell free
- newly diagnosed
- ejection fraction
- patients undergoing
- liver failure
- single molecule
- prognostic factors
- acute lymphoblastic leukemia
- emergency department
- respiratory failure
- intensive care unit
- magnetic resonance imaging
- genome wide association
- high throughput
- stem cells
- free survival
- dna methylation
- diffuse large b cell lymphoma
- oxidative stress
- aortic dissection
- adverse drug
- early life
- mechanical ventilation
- case control
- smoking cessation