Tumor necrosis factor and lymphotoxin alfa genetic polymorphisms and outcome in pediatric patients with non-Hodgkin's lymphoma: results from Berlin-Frankfurt-Münster Trial NHL-BFM 95.
OBJECTIVE
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.


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] > or = 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 > or = 500 U/L, CNS involvement, methotrexate infusion regimen), TNF -308/LT-alpha +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-alpha +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.


CONCLUSIONS
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 > or = 500 U/L, haplotype analysis further determined patients at risk for events.
Seidemann
Kathrin
K
Department of Pediatric Hematology and Oncology, Children's Hospital, Hannover Medical School, Hannover, Germany. kseidemann@web.de
Zimmermann
Martin
M
Book
Marion
M
Meyer
Ulrike
U
Burkhardt
Birgit
B
Welte
Karl
K
Reiter
Alfred
A
Stanulla
Martin
M
D000293:Adolescent; D001317:Austria / Q000453:epidemiology; D002648:Child; D018572:Disease-Free Survival; D005260:Female; D005858:Germany / Q000453:epidemiology; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000401:mortality; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D015999:Multivariate Analysis; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D016016:Proportional Hazards Models; D016019:Survival Analysis; D013557:Switzerland / Q000453:epidemiology; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha