Amara K, Trimeche M, Ziadi S, Laatiri A, Hachana M, Korbi S
Department of Pathology, Farhat-Hached Hospital of Sousse, Tunisia.
Ann Oncol. 2008 Oct;19(10):1774-86. doi: 10.1093/annonc/mdn374. Epub 2008 Jun 6.
Diffuse large B-cell lymphoma (DLBCL) exhibits heterogeneous clinical features and a marked variable response to treatment.
We investigated the prognostic significance of the methylation status of DAPK, GSTP1, P14, P15, P16, P33, RB1, SHP1, CDH1, APC, BLU, VHL, TIMP3, and RASSF1A genes in 46 DLBCL specimens from Tunisian patients. Methylation status of each gene was correlated with clinicopathological parameters including the International Prognostic Index (IPI), the germinal center immunophenotype, and response to treatment and survival. Overall survival (OS) and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method and differences were compared with the log-rank test.
Hypermethylation of SHP1 was associated with elevated lactate dehydrogenase level (P = 0.031). P16 and VHL were frequently hypermethylated in patients with high IPI scores (P = 0.006 and 0.004) and a performance status of two or more (P = 0.007 and 0.047). In addition, hypermethylation of P16 was significantly associated with advanced clinical stages and B symptoms (P = 0.041 and 0.012). Interestingly, hypermethylation of DAPK was significantly correlated with resistance to treatment (P = 0.023). With regard to survival rates, promoter hypermethylation of DAPK, P16, and VHL were significantly associated with shortened OS (P = 0.003, 0.001, and 0.017, respectively) and DFS (P = 0.006, 0.003, and 0.046, respectively). In multivariate analysis, hypermethylation of DAPK remains an independent prognostic factor in predicting shortened OS (P = 0.001) and DFS (P = 0.024), as well as the IPI and the germinal center status.
This study demonstrates that DLBCLs with hypermethylated P16, VHL, DAPK, and SHP1 commonly show a biologically aggressive phenotype and worse prognosis. Interestingly, hypermethylation of DAPK was found to be an independent prognostic factor that may be used in conjunction with the conventional prognostic factors such as the IPI and the germinal center status.
弥漫性大B细胞淋巴瘤（DLBCL）具有异质性临床特征，对治疗的反应差异显著。
我们研究了46例突尼斯患者的DLBCL标本中DAPK、GSTP1、P14、P15、P16、P33、RB1、SHP1、CDH1、APC、BLU、VHL、TIMP3和RASSF1A基因甲基化状态的预后意义。每个基因的甲基化状态与包括国际预后指数（IPI）、生发中心免疫表型、治疗反应和生存等临床病理参数相关。总生存（OS）率和无病生存（DFS）率采用Kaplan-Meier法计算，并通过对数秩检验比较差异。
SHP1的高甲基化与乳酸脱氢酶水平升高相关（P = 0.031）。P16和VHL在IPI评分高的患者（P = 0.006和0.004）以及体能状态为2级或更高的患者中经常发生高甲基化（P = 0.007和0.047）。此外，P16的高甲基化与晚期临床分期和B症状显著相关（P = 0.041和0.012）。有趣的是，DAPK的高甲基化与治疗抵抗显著相关（P = 0.023）。关于生存率，DAPK、P16和VHL的启动子高甲基化分别与缩短的OS（P = 0.003、0.001和0.017）和DFS（P = 0.006、0.003和0.046）显著相关。在多变量分析中，DAPK的高甲基化仍然是预测缩短的OS（P = 0.001）和DFS（P = 0.024）以及IPI和生发中心状态的独立预后因素。
本研究表明，P16、VHL、DAPK和SHP1高甲基化的DLBCL通常表现出生物学侵袭性表型和更差预后。有趣的是，发现DAPK的高甲基化是一个独立的预后因素，可与IPI和生发中心状态等传统预后因素结合使用。
