肿瘤坏死因子和淋巴毒素α基因多态性与儿童非霍奇金淋巴瘤患者的预后：来自柏林-法兰克福-明斯特试验NHL-BFM 95的结果

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.

作者信息

Seidemann Kathrin, Zimmermann Martin, Book Marion, Meyer Ulrike, Burkhardt Birgit, Welte Karl, Reiter Alfred, Stanulla Martin

机构信息

Department of Pediatric Hematology and Oncology, Children's Hospital, Hannover Medical School, Hannover, Germany.

出版信息

J Clin Oncol. 2005 Nov 20;23(33):8414-21. doi: 10.1200/JCO.2005.01.2179.

DOI:10.1200/JCO.2005.01.2179

PMID:16293872

Abstract

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] > 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.

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 > or = 500 U/L, haplotype analysis further determined patients at risk for events.

摘要

目的

分析肿瘤坏死因子（TNF -308 [G→A]）和淋巴毒素α（LT-α +252 [A→G]）基因内的遗传变异与儿童及青少年非霍奇金淋巴瘤预后的相关性。

患者与方法

对1996年4月至2000年1月参加德国 - 奥地利 - 瑞士多中心试验NHL - BFM 95的患者（n = 488）进行TNF -308（G→A）和LT-α +252（A→G）多态性基因分型，采用聚合酶链反应并随后对无肿瘤标本的DNA进行限制性片段长度多态性分析。

结果

在伯基特淋巴瘤（BL）和B细胞急性淋巴细胞白血病（B - ALL；n = 219，211例符合条件的患者）患者中，携带至少两个变异等位基因（高产单倍型）的患者发生事件的风险增加：3年无事件生存率（pEFS）为81%（SE = 5%），而低产单倍型患者为91%（SE = 2%）（P = 0.018）。在肿瘤负荷高（乳酸脱氢酶[LDH]≥500 U/L；n = 104）的BL/B - ALL中，高产单倍型患者的pEFS为69%（SE = 8%），低产单倍型患者为85%（SE = 4%）（P = 0.05）。在包括事件风险因素（LDH≥500 U/L、中枢神经系统受累、甲氨蝶呤输注方案）的多变量分析中，TNF -308/LT-α +252单倍型保持预后相关性：高产单倍型患者发生事件的风险增加2.34倍（P = 0.048）。TNF -308（G→A）和LT-α +252（A→G）多态性与淋巴细胞淋巴瘤（n = 101）、间变性大细胞淋巴瘤（n = 67）或弥漫性大B细胞淋巴瘤（n = 65）的pEFS无关，也与治疗相关毒性无关。