摘要

Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

译文

滤泡性淋巴瘤 (FL) 是一种惰性但无法治愈的 b细胞恶性肿瘤。一部分患者的死亡率因两个不同的临床终点而增加: 组织学转化和免疫化疗后的早期进展。导致这些临床终点的肿瘤克隆动力学的性质知之甚少,先前确定的基因改变并不能解释大多数转化病例或准确预测早期进展性疾病。我们认为,关于特定细胞群的扩张模式及其相关突变的详细知识将为 FL 临床历史的治疗策略和疾病生物学提供见解。在匹配的诊断和复发标本上使用全基因组测序、靶向深度测序和数字微滴 PCR 的组合,我们破译了 15 个转化案例和 6 个进展案例中的组成克隆群体,并测量了克隆群体丰度随时间的变化。我们观察到与进展病例相比,转化病例的克隆动力学模式差异很大。转化标本通常由诊断标本中罕见或缺失的克隆组成,与主导转化标本的戏剧性克隆扩张一致。这种模式与转化时间和治疗方式无关。相比之下,早期进展标本由已经存在于诊断标本中的克隆组成,即使在免疫化疗的情况下,也只表现出中等的克隆动力学。在一个由 395 名患者的 277 个样本组成的扩展队列中进行了影响 94 个基因的体细胞突变分析,以破译两个临床终点中被破坏的生物学。我们发现了 12 个基因,这些基因在转化样本中比在之前的 FL 肿瘤中更常见的突变,包括 TP53 、 B2M 、 CCND3 、 GNA13 、 S1PR2 和 P2RY8。此外,十个基因在早期进展的患者的诊断样本中更常见的突变,包括 TP53,BTG1,MKI67, 和 xbp1。我们的结果阐明了形成转化和进展的临床历史的对比进化模式。它们对治疗诱导的选择压力背景下的进化动力学的解释有影响,并表明转化和进展将需要不同的临床管理策略。

lymphoma

免疫 淋巴瘤 疾病
概述  :  

当身体发生恶性肿瘤时,免疫系统可被激活并识别杀伤肿瘤细胞,但免疫系统中的免疫细胞同样可以发生癌变,当免疫系统中的淋巴细胞或淋巴组织发生癌变时称为淋巴瘤,淋巴瘤是威胁人类健康的血液系统恶性肿瘤之一,其发病率逐年增加,淋巴系统包括淋巴结、淋巴管、脾脏、胸腺、扁桃腺以及胃肠器官的淋巴组织等,上述组织原发的癌变称为淋巴瘤,其以无痛性、进行性的淋巴结肿大和局部肿块为特征性表现。目前绝大多数病理类型的淋巴瘤发病原因尚不明确。 病因及发病机制

lymphoma 英 [lim’fəʊmə] 美 [lim’foʊmə]

释    义    n.淋巴瘤

例    句    The lymphomas are divided into two major categories: Hodgkin lymphoma and all other lymphomas, called non-Hodgkin lymphomas.淋巴瘤可分为两大类:霍奇金淋巴瘤和其他的淋巴瘤,被称作非霍奇金淋巴瘤。

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