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 (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G>A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.

Figure 1

Low-risk MTX therapy. A punctured line indicates that not all patients received this specific dose. In maintenance therapy, 6-mercaptopurine (6-MP) and MTX are administered in low oral doses. MTX (8-12 mg) was administered intrathecally 6 times before consolidation.

Figure 2

High-risk MTX therapy. A punctured line indicates that not all patients received this specific dose. In maintenance therapy, 6-mercaptopurine (6-MP) and MTX were administered in low oral doses. MTX (8-12 mg) was administered intrathecally 6 times before consolidation.

Figure 3

RFC polymorphism and outcome. The Kaplan-Meier survival curve is shown to visualize the difference between AA variant and GG/GA variants (log-rank P = .046).

Figure 4

RFC polymorphism, outcome, and relation to chromosome 21. (A) Outcome in patients with a normal copy number of chromosome 21. Patients with an increased copy number of chromosome 21 (expected higher MTX influx) had no significant differences among RFC variants (P = .94; data not shown). (B) Different hazard ratios compared with patients with a normal copy number of chromosome 21 and RFC80 GA/GG variant according to the NOPHO 92 protocol.