Prognostic implications of 5-hydroxymethylcytosines from circulating cell-free DNA in diffuse large B-cell lymphoma
Prognostic implications of 5-hydroxymethylcytosines from circulating cell-free DNA in diffuse large B-cell lymphoma
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DOI：
10.1182/bloodadvances.2019000175
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发表时间：
2019-10-08
期刊：
影响因子：
7.5
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Chiu, Brian C-H;Zhang, Zhou;Zhang, Wei
在弥漫性大B细胞淋巴瘤（DLBCL）中，循环游离DNA（cfDNA）水平升高与肿瘤体积和预后不良相关，但cfDNA中具有预后意义的肿瘤特异性分子改变仍不清楚。我们研究了来自血浆的cfDNA中的5-羟甲基胞嘧啶（5 hmC）（活性去甲基化和基因活化的标志物）与新诊断的DLBCL患者的预后之间的关联。我们使用5 hmC-Seal（一种高度敏感的化学标记技术）分析了2010年至2013年期间芝加哥大学医学中心48名DLBCL患者血浆cfDNA中的全基因组5 hmC。患者随访至2017年12月31日。我们在cfDNA标记组织特异性增强子中发现了5 hmC的独特基因组分布，这与它们在基因调控中的假定作用一致。cfDNA中的5 hmC谱因细胞来源而异，并与临床预后因素相关，包括分期和国际预后指数。我们通过对考克斯比例风险模型应用弹性网络正则化，开发了一种基于29个基因的加权预后评分（wp评分），用于预测无事件生存期（EFS）和总生存期（OS）。在多变量考克斯模型中，与低风险组相比，高wp评分的患者EFS更差（风险比，9.17; 95%置信区间，2.01-41.89; P = .004）。我们的研究结果表明，诊断时cfDNA中的5 hmC标签与临床结果相关，并可能为DLBCL提供一种新的微创预后方法。
An elevated level of circulating cell-free DNA (cfDNA) has been associated with tumor bulk and poor prognosis in diffuse large B-cell lymphoma (DLBCL), but the tumor-specific molecular alterations in cfDNA with prognostic significance remain unclear. We investigated the association between 5-hydroxymethylcytosines (5hmC), a mark of active demethylation and gene activation, in cfDNA from blood plasma and prognosis in newly diagnosed DLBCL patients. We used 5hmC-Seal, a highly sensitive chemical labeling technique, to profile genome-wide 5hmC in plasma cfDNA from 48 DLBCL patients at the University of Chicago Medical Center between 2010 and 2013. Patients were followed through 31 December 2017. We found a distinct genomic distribution of 5hmC in cfDNA marking tissue-specific enhancers, consistent with their putative roles in gene regulation. The 5hmC profiles in cfDNA differed by cell of origin and were associated with clinical prognostic factors, including stage and the International Prognostic Index. We developed a 29 gene-based weighted prognostic score (wp-score) for predicting event-free survival (EFS) and overall survival (OS) by applying the elastic net regularization on the Cox proportional-hazards model. The wp-scores outperformed (eg, prognostic accuracy, sensitivity, specificity) established prognostic factors in predicting EFS and OS. In multivariate Cox models, patients with high wp-scores had worse EFS (hazard ratio, 9.17; 95% confidence interval, 2.01-41.89; P = .004) compared with those in the low-risk group. Our findings suggest that the 5hmC signatures in cfDNA at the time of diagnosis are associated with clinical outcomes and may provide a novel minimally invasive prognostic approach for DLBCL.