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 () 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 (DNA-TG/Ery-TGN ratio) was significantly associated with three intronic SNPs in NT5C2 (top hit: rs72846714; P = 2.09 × 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 and 1.3 × 10, respectively). The association was mostly driven by differences in Ery-TGN, but in regression analyses adjusted forEry-TGN (P < 0.0001), rs72846714-A genotype was also associated with a higher DNA-TG (P = 0.029). Targeted sequencing of NT5C2 did not identify any missense variants associated with rs72846714 orEry-TGN/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.

Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL

“…3,6 Interestingly, rs72846714, an intronic single-nucleotide polymorphism in the NT5C2 locus is associated with the propensity for thioguanine DNA incorporation in ALL patients. 35 Although rs72846714-A is not associated with increased ALL relapse risk, it has been linked with increased occurrence of gain-of-function NT5C2 relapse-specific mutations, supporting a potential interaction between somatic and germline variants in driving increased NT5C2 activity. 35…”

“…35 Although rs72846714-A is not associated with increased ALL relapse risk, it has been linked with increased occurrence of gain-of-function NT5C2 relapse-specific mutations, supporting a potential interaction between somatic and germline variants in driving increased NT5C2 activity. 35…”

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

“…If such knowledge could be established in the future, it may help better understand the efficacy of individual drugs in the context of COVID-19. For example, a SNP on NT5C2, present in 15% of the population, significantly affected the cellular activity of thiopurine and its incorporation into DNA 55 . Our results would similarly suggest that patients with such genetic variation may respond differently to remdesivir and favipiravir, but not to ribavirin (Fig.…”

Genome wide association studies for treatment‐related adverse effects of pediatric acute lymphoblastic leukemia

“…The association of rs72846714 was replicated also in the validation cohort (555 patients) both in early and late maintenance ( p = 8.4 × 10 −6 and 1.3 × 10 −3 , respectively). SNP rs72846714 was not associated with relapse risk, but in a separate cohort of 180 children with relapsed ALL, the rs72846714 AA genotype was associated to an increased occurrence of relapse ( p = .03) (Tulstrup et al, 2018). NT5C2 is an enzyme that regulates intracellular levels of purine monophosphates; during thiopurine treatment it can affect the levels of available TGNs.…”