Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study
Mutational Landscape and Tumor Burden Assessed by Cell-free DNA in Diffuse Large B-Cell Lymphoma in a Population-Based Study
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DOI：
10.1158/1078-0432.ccr-20-2558
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发表时间：
2021-01-15
影响因子：
11.5
通讯作者：
Lopez-Guillermo, Armando
中科院分区：
文献类型：
--
作者：
Rivas-Delgado, Alfredo;Nadeu, Ferran;Lopez-Guillermo, Armando
目的：我们分析了无细胞DNA(CfDNA)在基于人群的前瞻性队列中的应用，以确定弥漫性大B细胞淋巴瘤(DLBCL)患者的突变情况，评估肿瘤负荷，并评估其对应答率和预后的影响。实验设计：在研究期间，共有100名患者被诊断为DLBCL。采用下一代靶向测序技术研究了cfDNA中112个基因的突变情况。结果：在100例患者中，有79例获得了适合进行分析的cfDNA。79例患者中有69例(87%)至少检测到一种突变。CfDNA检测突变的敏感性为68%(95%可信区间为56.2~78.7)。在cfDNA样本中发现的突变情况与组织中显示的高度一致，并允许43%的病例进行遗传分类。高水平的循环肿瘤DNA(CtDNA)与肿瘤负荷相关的临床参数(乳酸脱氢酶和β2微球蛋白水平升高、晚期和高危国际预后指数)和PET/CT评估的总代谢性肿瘤体积显著相关。在有治疗意图的患者中，高ctDNA水平(2.5logHGE/mL)与较低的完全应答率(65%比96%；P<；0.004)、较短的无进展生存期(65%比85%；P=0.038)和总存活率(73%比100%；P=0.007)，尽管在多变量分析中没有维持预后价值。结论：在一项基于人群的前瞻性DLBCL序列中，cfDNA可作为评估肿瘤负担、确定肿瘤突变情况和基因分类的替代来源，这具有预后意义，并可能有助于未来的个体化治疗。
Purpose: We analyzed the utility of cell-free DNA (cfDNA) in a prospective population-based cohort to determine the mutational profile, assess tumor burden, and estimate its impact in response rate and outcome in patients with diffuse large B-cell lymphoma (DLBCL).Experimental Design: A total of 100 patients were diagnosed with DLBCL during the study period. Mutational status of 112 genes was studied in cfDNA by targeted next-generation sequencing. Paired formalin-fixed, paraffin-embedded samples and volumetric PET/CT were assessed when available.Results: Appropriate cfDNA to perform the analyses was obtained in 79 of 100 cases. At least one mutation could be detected in 69 of 79 cases (87%). The sensitivity of cfDNA to detect the mutations was 68% (95% confidence interval, 56.2-78.7). The mutational landscape found in cfDNA samples was highly consistent with that shown in the tissue and allowed genetic classification in 43% of the cases. A higher amount of circulating tumor DNA (ctDNA) significantly correlated with clinical parameters related to tumor burden (elevated lactate dehydrogenase and beta 2-microglobulin serum levels, advanced stage, and high-risk International Prognostic Index) and total metabolic tumor volume assessed by PET/CT. In patients treated with curative intent, high ctDNA levels (>2.5 log hGE/mL) were associated with lower complete response (65% vs. 96%; P < 0.004), shorter progression-free survival (65% vs. 85%; P = 0.038), and overall survival (73% vs. 100%; P = 0.007) at 2 years, although it did not maintain prognostic value in multivariate analyses.Conclusions: In a population-based prospective DLBCL series, cfDNA resulted as an alternative source to estimate tumor burden and to determine the tumor mutational profile and genetic classification, which have prognostic implications and may contribute to a future tailored treatment.