文章：

从遗传学到临床：滤泡性淋巴瘤的翻译视角

From genetics to the clinic: a translational perspective on follicular lymphoma

原文发布日期：2018-02-09

DOI: 10.1038/nrc.2017.127

类型: Review Article

开放获取: 否

要点：

1. Follicular lymphoma (FL) is a generally indolent but incurable disease characterized by multiple episodes of disease progression.
2. Cells bearing the t(14;18) translocation follow iterative transits through germinal centres upon successive immunological challenges before undergoing FL-associated developmental arrest. They accumulate deleterious genomic alterations leading to overt FL over an extended period of time (probably decades).
3. In situ follicular neoplasia and partial involvement by FL represent the earliest tumour stages identified to date.
4. Mutations in epigenetic modifiers arise in nearly 90% of patients with FL and likely represent an early event in lymphomagenesis. Survival pathways such as B cell receptor (BCR), mTOR complex 1 (mTORC1) or Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling, as well as proteins implicated in escape from immune surveillance, are also frequently affected by mutations.
5. Disease progression and histological transformation exhibit different clonal dynamics that are driven by distinct evolutionary mechanisms. The acquisition of a transformed phenotype through divergent evolution might not be predictable at the time of diagnosis.
6. In addition to immunotherapy, inhibitors of methyltransferases, histone deacetylases, the BCR signalling pathway and mTORC1 represent potential therapeutic options being investigated.

要点翻译：

1. 滤泡性淋巴瘤（FL）通常是一种惰性但无法治愈的疾病，其特征是多次疾病进展。
2. 携带t(14;18)易位的细胞在经历FL相关的发育停滞之前，会随着连续免疫挑战在生发中心经历反复穿梭。在较长时间（可能数十年）内，这些细胞积累有害的基因组改变，最终发展为显性FL。
3. 原位滤泡性肿瘤和FL部分受累是迄今发现的最早肿瘤阶段。
4. 表观遗传修饰因子突变出现在近90%的FL患者中，可能是淋巴瘤发生过程中的早期事件。BCR受体、mTORC1复合物、JAK-STAT信号通路等生存途径，以及参与免疫逃逸的蛋白也常受突变影响。
5. 疾病进展和组织学转化表现出不同的克隆动态，由不同的进化机制驱动。通过分化进化获得转化表型可能在诊断时无法预测。
6. 除免疫治疗外，甲基转移酶抑制剂、组蛋白去乙酰化酶抑制剂、BCR信号通路抑制剂和mTORC1抑制剂是目前正在研究的潜在治疗选择。

英文摘要：

Follicular lymphoma (FL) is the most frequent indolent B cell lymphoma and is still considered to be incurable. In recent years, whole-exome sequencing studies of large cohorts of patients have greatly improved our knowledge of the FL mutational landscape. Moreover, the prolonged evolution of this disease has enabled some insights regarding the early pre-lymphoma lesions as well as the clonal evolution after treatment, allowing an evolutionary perspective on lymphomagenesis. Deciphering the earliest initiating lesions and identifying the molecular alterations leading to disease progression currently represent important goals; accomplishing these could help identify the most relevant targets for precision therapy.

摘要翻译： 

滤泡性淋巴瘤（FL）是最常见的惰性B细胞淋巴瘤，目前仍被视为不可治愈。近年来，通过对大样本患者进行全外显子组测序研究，我们对FL的突变谱有了更深入的了解。此外，由于该疾病病程较长，研究者得以观察到淋巴瘤前期的早期病变以及治疗后的克隆演化，从而从进化角度理解淋巴瘤的发生。当前的重要目标是揭示最早的起始性病变，并识别导致疾病进展的分子改变；实现这些目标将有助于发现精准治疗中最相关的靶点。

原文链接：

From genetics to the clinic: a translational perspective on follicular lymphoma