Kristensen Lasse Sommer, Asmar Fazila, Dimopoulos Konstantinos, Nygaard Mette Kathrine, Aslan Derya, Hansen Jakob Werner, Ralfkiaer Elisabeth, Grønbæk Kirsten
Department of Haematology, Rigshospitalet, Blegdamsvej 9, 2100-DK, Copenhagen, Denmark.
Department of Haematology, Aalborg University Hospital, Mølleparkvej 4, 9000-DK, Aalborg, Denmark.
Oncotarget. 2014 Oct 30;5(20):9798-810. doi: 10.18632/oncotarget.2394.
Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma. Improvements in overall survival have been observed with the introduction of rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), however, prognostic markers are still needed. Methylation of the death associated protein kinase (DAPK or DAPK1) gene and TP53 mutations are likely to have prognostic value in DLBCL. We have assessed TP53 mutations and allelic DAPK1 methylation patterns in a cohort of 119 DLBCL patients uniformly treated with R-CHOP-like regimens. We found that DAPK1 promoter methylation was associated with shorter overall survival (p=0.017) and disease-specific survival (p=0.023). In multivariate analyses DAPK1 methylation remained as an independent prognostic factor predicting disease-specific survival (p=0.038). When only considering individuals heterozygous for the rs13300553 SNP monoallelic methylation of the A-allele was associated with shorter overall- and disease-specific survival (p<0.001). Patients carrying both DAPK1 methylation and a TP53 mutation had an inferior survival compared to patients carrying only one of these molecular alterations, however, this was borderline statistically significant. Allele-specific DAPK1 methylation patterns were also studied in a cohort of 67 multiple myeloma patients, and all of the methylated multiple myeloma samples heterozygous for the rs13300553 SNP were methylated on both alleles.
弥漫性大B细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤类型。随着利妥昔单抗联合环磷酰胺、阿霉素、长春新碱和泼尼松（R-CHOP）方案的引入，总体生存率有所提高，然而，仍需要预后标志物。死亡相关蛋白激酶（DAPK或DAPK1）基因的甲基化和TP53突变可能对DLBCL具有预后价值。我们评估了119例接受R-CHOP样方案统一治疗的DLBCL患者队列中的TP53突变和DAPK1等位基因甲基化模式。我们发现DAPK1启动子甲基化与较短的总生存期（p=0.017）和疾病特异性生存期（p=0.023）相关。在多变量分析中，DAPK1甲基化仍然是预测疾病特异性生存期的独立预后因素（p=0.038）。仅考虑rs13300553 SNP杂合个体时，A等位基因的单等位基因甲基化与较短的总生存期和疾病特异性生存期相关（p<0.001）。与仅携带这些分子改变之一的患者相比，同时携带DAPK1甲基化和TP53突变的患者生存期较差，然而，这在统计学上接近显著。我们还在一组67例多发性骨髓瘤患者中研究了等位基因特异性DAPK1甲基化模式，并且所有rs13300553 SNP杂合的甲基化多发性骨髓瘤样本在两个等位基因上均发生甲基化。
