Purpose To analyze the association of genetic variation within the tumor necrosis factor (TNF −308 [G→A]) and lymphotoxin alfa (LT-a +252 [A→G]) genes with outcome in non-Hodgkin's lymphoma of childhood and adolescence. Patients and Methods Genotyping of the TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms in patients (n = 488) enrolled onto the German-Austrian-Swiss multicenter trial NHL-BFM 95 from April 1996 to January 2000 was performed by polymerase chain reaction with subsequent restriction fragment length polymorphism analysis on DNA from tumor-free specimen. Results In patients with Burkitt's lymphoma (BL) and B-cell acute lymphoblastic leukemia (B-ALL; n = 219, 211 eligible patients), patients carrying at least two variant alleles (high-producer haplotypes) had an increased risk of events: probability of event-free survival (pEFS) at 3 years was 81% (SE = 5%), compared with 91% (SE = 2%) in low-producer haplotypes (P = .018). In BL/B-ALL with high tumor load (lactate dehydrogenase [LDH] ≥ 500 U/L; n = 104), pEFS was 69% (SE = 8%) in high-producer versus 85% (SE = 4%) in low-producer haplotypes (P = .05). In multivariate analysis including risk factors for events (LDH ≥ 500 U/L, CNS involvement, methotrexate infusion regimen), TNF −308/LT-α +252 haplotype kept prognostic relevance: patients with high-producer haplotypes had a 2.34-fold increase in risk of events (P = .048). The TNF −308 (G→A) and LT-α +252 (A→G) polymorphisms were not associated with pEFS in lymphoblastic lymphoma (n = 101), anaplastic large-cell lymphoma (n = 67), or diffuse large B-cell lymphoma (n = 65), nor with therapy-related toxicity. Conclusion The TNF −308 (G→A) and LT-a +252 (A→G) polymorphisms were negative prognostic factors in pediatric BL/B-ALL. Among patients with serum LDH ≥ 500 U/L, haplotype analysis further determined patients at risk for events.
Tumor necrosis factor- and interleukin-6-producing high-grade B-cell lymphoma, not otherwise specified in the pleura
