The association of reduced folate carrier 80G>A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number

Abstract

The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G>A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P ‫؍‬ .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (plate-

Childhood Acute Lymphoblastic Leukemia: Progress Through Collaboration

“…Initially, by using genome-wide gene expression arrays, the expression (mRNA) of a relatively small number of genes in leukemia cells was linked to de novo sensitivity of glucocorticoids, vincristine, daunorubicin, and L-asparaginase, 70 multidrug crossresistance, 71 in vivo response to initial treatment with high-dose methotrexate, 72 and inherited genome variants related to response to remission induction therapy. 73 Indeed, both germline and somatic genome variation can influence the effects of ALL chemotherapy, [74][75][76][77][78] which emphasizes the importance of assessing both inherited and somatic genome variation in cancer pharmacogenomics. Furthermore, genome-wide mRNA expression analyses have identified genome variation that influences the accumulation of the active polyglutamylated metabolites of methotrexate in ALL cells after in vivo methotrexate treatment.…”

Germline genetic variations in methotrexate candidate genes are associated with pharmacokinetics, toxicity, and outcome in childhood acute lymphoblastic leukemia

“…[18][19][20][21][22] rs1051266 in SLC19A1, resulting in a less efficient transporter, has been associated with more adverse events and worse overall prognosis. [23][24][25][26] A polymorphic tandem repeat in the 59UTR of the TYMS enhancer region (rs34743033) was associated with a significantly greater chance of response to treatment in 205 ALL patients treated with MTX. 27 A genome-wide association study implicated the intronic SNP rs11045879 in the SLCO1B1 transporter gene, which was in linkage disequilibrium (LD) with the functional SLCO1B1 SNP rs4149056, with MTX clearance and gastrointestinal toxicity in 640 ALL patients.…”

Methotrexate binds to recombinant thiopurine S-methyltransferase and inhibits enzyme activity after high-dose infusions in childhood leukaemia

“…Median (interquartile range) pre-HDMTX infusion TPMT (U/ml pRBC), RBC TGN and meTIMP levels (pmol/8x10 8 …”

“…Both 6-MP and MTX inhibit de novo purine synthesis (DNPS) and the combination of 6-MP and MTX leads to a pronounced DNPS inhibition in vivo, compared to 6-MP or MTX alone [7].The interaction between the drugs is complex and cellular response to the drugs is prompt. In addition, genetic polymorphisms in gene encoding transporters (such as the reduced folate carrier) and enzymes involved in MTX uptake and metabolism affect the treatment outcomes and toxicity [8]. Recombinant protein was used to investigate binding of MTX to the TPMT protein and a leukaemic cell line to study effects on TPMT enzyme activity in vitro.…”