Institute for Cancer Genetics.
Department of Pathology and Cell Biology.
Blood. 2018 May 24;131(21):2307-2319. doi: 10.1182/blood-2017-11-764332. Epub 2018 Apr 17.
Diffuse large B-cell lymphoma (DLBCL), the most frequent subtype of lymphoid malignancy, remains a significant clinical challenge, as ∼30% of patients are not cured. Over the past decade, remarkable progress has been made in the understanding of the pathogenesis of this disease, spurred by the implementation of powerful genomic technologies that enabled the definition of its genetic and epigenetic landscape. These studies have uncovered a multitude of genomic alterations that contribute to the initiation and maintenance of the tumor clone by disrupting biological functions known to be critical for the normal biology of its cells of origin, germinal center B cells. The identified alterations involve epigenetic remodeling, block of differentiation, escape from immune surveillance, and the constitutive activation of several signal transduction pathways. This wealth of new information offers unique opportunities for the development of improved diagnostic and prognostic tools that could help guide the clinical management of DLBCL patients. Furthermore, a number of the mutated genes identified are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. This review summarizes current knowledge of the most common genetic alterations associated with DLBCL in relation to their functional impact on the malignant transformation process, and discusses their clinical implications for mechanism-based therapeutics.
弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的淋巴恶性肿瘤亚型，仍然是一个重大的临床挑战，因为约 30%的患者无法治愈。在过去的十年中，由于实施了强大的基因组技术，能够定义其遗传和表观遗传景观，对这种疾病发病机制的理解取得了显著进展。这些研究揭示了许多基因组改变，通过破坏已知对其起源细胞——生发中心 B 细胞的正常生物学至关重要的生物学功能，促进了肿瘤克隆的起始和维持。确定的改变涉及表观遗传重塑、分化阻断、逃避免疫监视和几个信号转导途径的组成性激活。这些丰富的新信息为开发改进的诊断和预后工具提供了独特的机会，这些工具可以帮助指导 DLBCL 患者的临床管理。此外，目前正在探索许多已鉴定的突变基因作为潜在的治疗靶点，用于开发新的治疗策略。这篇综述总结了与恶性转化过程中对其功能影响相关的最常见的与 DLBCL 相关的遗传改变的最新知识，并讨论了它们对基于机制的治疗的临床意义。
