Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study
Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study
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DOI：
10.1182/blood-2012-05-433334
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发表时间：
2012-11-08
期刊：
影响因子：
20.3
通讯作者：
Young, Ken H.
中科院分区：
文献类型：
--
作者：
Xu-Monette, Zijun Y.;Wu, Lin;Young, Ken H.
TP 53突变是接受环磷酰胺、羟基柔红霉素、长春新碱和泼尼松（CHOP）治疗的弥漫性大B细胞淋巴瘤（DLBCL）患者预后不良的独立标志物。然而，它在利妥昔单抗免疫化疗时代的预后价值仍然不确定。在本研究中，一个大型队列的DLBCL患者接受利妥昔单抗联合CHOP（R-CHOP）治疗，我们发现，与没有TP 53突变的患者相比，TP 53突变的患者总体生存率和无进展生存率更差。与早期CHOP治疗患者的研究不同，TP 53突变对R-CHOP治疗的生发中心B细胞或活化B细胞DLBCL亚型患者具有预测价值。此外，我们确定了DNA结合结构域中的环-片-螺旋和L3基序是维持p53功能的最关键结构。相反，TP 53缺失和杂合性缺失并没有导致更差的生存率。如果基因突变数据不可用，免疫组化分析显示> 50%的细胞表达p53蛋白是一个有用的替代品，能够对具有显著不同病变的患者进行分层。我们的结论是，TP 53突变状态的评估是重要的分层R-CHOP治疗的患者到不同的预后亚组，并在未来的治疗策略的设计具有重要的价值。（血。2012;120（19）：3986-3996）
TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies. (Blood. 2012;120(19):3986-3996)