Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
J Intern Med. 2017 Nov;282(5):371-394. doi: 10.1111/joim.12633. Epub 2017 Jun 20.
With the introduction of next-generation sequencing, the genetic landscape of the complex group of B-cell lymphoid malignancies has rapidly been unravelled in recent years. This has provided important information about recurrent genetic events and identified key pathways deregulated in each lymphoma subtype. In parallel, there has been intense search and development of novel types of targeted therapy that 'hit' central mechanisms in lymphoma pathobiology, such as BTK, PI3K or BCL2 inhibitors. In this review, we will outline the current view of the genetic landscape of selected entities: follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukaemia and marginal zone lymphoma. We will detail recurrent alterations affecting important signalling pathways, that is the B-cell receptor/NF-κB pathway, NOTCH signalling, JAK-STAT signalling, p53/DNA damage response, apoptosis and cell cycle regulation, as well as other perhaps unexpected cellular processes, such as immune regulation, cell migration, epigenetic regulation and RNA processing. Whilst many of these pathways/processes are commonly altered in different lymphoid tumors, albeit at varying frequencies, others are preferentially targeted in selected B-cell malignancies. Some of these genetic lesions are either involved in disease ontogeny or linked to the evolution of each disease and/or specific clinicobiological features, and some of them have been demonstrated to have prognostic and even predictive impact. Future work is especially needed to understand the therapy-resistant disease, particularly in patients treated with targeted therapy, and to identify novel targets and therapeutic strategies in order to realize true precision medicine in this clinically heterogeneous patient group.
随着下一代测序技术的引入，近年来，B 细胞淋巴样恶性肿瘤这一复杂群体的遗传特征迅速被揭示。这为了解反复发生的遗传事件以及确定每种淋巴瘤亚型中失调的关键途径提供了重要信息。与此同时，人们一直在积极寻找和开发新型靶向治疗方法，这些方法针对淋巴瘤病理生物学中的核心机制，如 BTK、PI3K 或 BCL2 抑制剂。在这篇综述中，我们将概述选定实体的遗传特征的当前观点：滤泡性淋巴瘤、弥漫性大 B 细胞淋巴瘤、套细胞淋巴瘤、慢性淋巴细胞白血病和边缘区淋巴瘤。我们将详细描述影响重要信号通路的反复改变，即 B 细胞受体/NF-κB 通路、NOTCH 信号通路、JAK-STAT 信号通路、p53/DNA 损伤反应、细胞凋亡和细胞周期调控，以及其他可能意想不到的细胞过程，如免疫调节、细胞迁移、表观遗传调控和 RNA 处理。虽然这些通路/过程在不同的淋巴肿瘤中经常发生改变，尽管频率不同，但其他过程在某些 B 细胞恶性肿瘤中被优先靶向。这些遗传病变中的一些与疾病的发生或与每种疾病和/或特定临床生物学特征的演变有关，其中一些已被证明具有预后甚至预测影响。未来的工作特别需要了解耐药性疾病，特别是接受靶向治疗的患者的耐药性疾病，并确定新的靶点和治疗策略，以便在这个临床异质性患者群体中实现真正的精准医学。
