Early progression after the first-line R-CHOP treatment leads to a very dismal outcome and necessitates alternative treatment for patients with diffuse large B-cell lymphoma (DLBCL). This study aimed to develop a genetic predictive model for early progression and evaluate its potential in advancing alternative treatment. Thirty-two hotspot driver genes were examined in 145 DLBCL patients and 5 DLBCL cell lines using next-generation sequencing. The association of clinical features, cell-of-origin, double expression, positive p53 protein, and gene alterations with early progression was analyzed, and the genetic predictive model was developed based on the related independent variables and assessed by the area under receiver operating characteristic. The potential of novel treatment based on the modeling was investigated in in-vitro DLBCL cell lines and in vivo xenograft mouse models. The frequency of CD79B (42.86% vs 9.38%, p = 0.000) and PIM1 mutations (38.78% vs 17.71%, p = 0.005) showed a significant increase in patients with early progression. CD79B and PIM1 mutations were associated with complex genetic events, double expression, non-GCB subtype, advance stage and unfavorable prognosis. A powerful genetic predictive model (AUROC = 0.771, 95% CI: 0.689–0.853) incorporating lactate dehydrogenase levels (OR = 2.990, p = 0.018), CD79B mutations (OR = 5.970, p = 0.001), and PIM1 mutations (OR = 3.021, p = 0.026) was created and verified in the other cohort. This modeling for early progression outperformed the prediction accuracy of conventional International Prognostic Index, and new molecular subtypes of MCD and Cluster 5. CD79B and PIM1 mutations indicated a better response to inhibitors of BTK (ibrutinib) and pan-PIM kinase (AZD 1208) through repressing activated oncogenic signaling. Since the two inhibitors failed to decrease BCL2 level, BCL2 inhibitor (venetoclax) was added and demonstrated to enhance their apoptosis-inducing activity in mutant cells with double expression. The genetic predictive model provides a robust tool to identify early progression and determine precision treatment. These findings warrant the development of optimal alternative treatment in clinical trials.

中文翻译：

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早期进展弥漫性大 B 细胞淋巴瘤精准治疗的遗传预测模型。

一线 R-CHOP 治疗后的早期进展导致非常糟糕的结果，需要对弥漫性大 B 细胞淋巴瘤 (DLBCL) 患者进行替代治疗。本研究旨在开发一种用于早期进展的遗传预测模型，并评估其在推进替代治疗方面的潜力。使用下一代测序在 145 名 DLBCL 患者和 5 个 DLBCL 细胞系中检测了 32 个热点驱动基因。分析临床特征、细胞来源、双表达、阳性p53蛋白和基因改变与早期进展的关系，并基于相关自变量建立遗传预测模型，并通过受试者工作特征下的面积进行评估. 在体外 DLBCL 细胞系和体内异种移植小鼠模型中研究了基于建模的新型治疗的潜力。CD79B（42.86% vs 9.38%，p = 0.000）和PIM1突变（38.78% vs 17.71%，p = 0.005）的频率显示早期进展患者显着增加。CD79B和PIM1突变与复杂的遗传事件、双重表达、非GCB亚型、晚期和不良预后相关。一个强大的遗传预测模型 (AUROC = 0.771, 95% CI: 0.689–0.853)，包含乳酸脱氢酶水平 (OR = 2.990, p = 0.018)、CD79B 突变 (OR = 5.970, p = 0.001) 和 PIM1 突变 (OR = 3.021，p = 0.026）在另一个队列中创建和验证。这种早期进展建模优于传统国际预后指数的预测准确性，以及 MCD 和簇 5 的新分子亚型。CD79B 和 PIM1 突变表明通过抑制激活的致癌信号传导对 BTK 抑制剂（依鲁替尼）和泛 PIM 激酶（AZD 1208）有更好的反应。由于这两种抑制剂未能降低 BCL2 水平，因此添加 BCL2 抑制剂 (venetoclax) 并证明可增强其在具有双重表达的突变细胞中的凋亡诱导活性。遗传预测模型为识别早期进展和确定精准治疗提供了强大的工具。这些发现保证了在临床试验中开发最佳替代疗法。由于这两种抑制剂未能降低 BCL2 水平，因此添加 BCL2 抑制剂 (venetoclax) 并证明可增强其在具有双重表达的突变细胞中的凋亡诱导活性。遗传预测模型为识别早期进展和确定精准治疗提供了强大的工具。这些发现保证了在临床试验中开发最佳替代疗法。由于这两种抑制剂未能降低 BCL2 水平，因此添加 BCL2 抑制剂 (venetoclax) 并证明可增强其在具有双重表达的突变细胞中的凋亡诱导活性。遗传预测模型为识别早期进展和确定精准治疗提供了强大的工具。这些发现保证了在临床试验中开发最佳替代疗法。